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171 Cards in this Set
- Front
- Back
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What is the major entry point for pathogens into the body
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The mucous membranes
The potential for antigen stimulation is huge and the physiological function of most of the mucosal organs is essential for life, only limited amounts of damage can be tolerated |
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What part of the body contains more lymphocytes than any other
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The mucosal tissues
a number of chronic diseases of mucosal surfaces seem to have an immunopathological basis |
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Organized Mucosa Associated Lymphoid Tissue (O-MALT)
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specialized local inductive sites on the mucosal immune system
This are the special INDUCTIVE SITES. The EFFECTOR sites are called Diffuse Mucosa-Associated Lymphoid Tissue (D-MALT) |
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O-MALT
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Organized Mucosa Associated Lymphoid Tissue
haracterized by lymphoid follicles. Follicles are aggregates of unstimulated B cells. If they are activated by an antigen, a germinal center of proliferating B cells is formed and the follicle is called a secondary follicle Single follicles occur along the entire length of the GI tract, with increasing frequency in the colon and rectum Associated with these follicles are adjacent areas containing T cell, dendritic cells and macrophages (In the gut OMAL = GALT..Gut associated...) |
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Peyer's Patches
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O-MALT in the gut is called GMALT.
Peyer's Patches are organized lymph nodules. They are aggregations of lymphoid tissue that are usually found in the lowest portion of the small intestine, the ileum, in humans; as such, they differentiate the ileum from the duodenum and jejunum They're covered by an epithelial layer containing specialized cells called M cells which have characteristic membrane ruffles |
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What is the major OMALT tissue in intranasal and for inhaled antigens
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The tonsils and adenoids (pharyngeal tonsils)
These form a physical barrier known as "Waldeyer's Ring" or the nasopharygeal associated lymphoreticular tissue (NALT) |
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BALT
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Bronchial-Associated Lymphoid Tissue
It's what you call MALT in the respiratory tract (kind of like how you call the gut associated MALTs GALT.) etc |
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What 2 compartments do non-encapsulated lymphoid tissues of the D-MALT contain unorganized collections of lymphocytes, plasma cells and macrophages
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The epithelium contains Intraepithelial Lymphocytes (IELs) which are mostly T lymphocytes. These are CD8+ T Cells that function like cytotoxic T Cells
The Lamina propria (LP) is a submucosal layer of connective tissue found directly under the basement membrane of many epithelial surfaces. It contains most components of the immune system with large numbers of B cells, plasma cells, macrophages, dendritic cells and T Cells |
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What makes up the effector sites of the mucosal immune response
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The scattered lamina propria and intraepithelial lymphocytes of the D-MALT
D-MALT = Diffuse Mucosa-Associated lymphoid Tissue |
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Peyer's Patches (more detail)
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consist of 30-40 lymphoid nodules on the outer wall of the intestines. They contain B cell follicles, T cells and dendritic cells
The are separated from the lumen of intestine by a single layer of epithelial cells and are organized structures very much like lymph nodes |
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M Cells
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special cells in the epithelium overlying Peyer's Patches (follicle-associated epithelium; FAE)
Their function is to take up and transport antigen to the underlying lymphoid tissue. They uptake by endocytosis/phagocytosis and transport antigens in vesicles to the basolateral side M = Microfolds, which are present on their luminal surface Their apical side is exposed to the lumen of the intestine. The basal surface contains a deeply invaginated pocket that has B cells, T cells and phagocytic cells |
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True or False
Dendritic Cells in addition to M cells can capture antigens directly from the intestinal lumen |
True
They reach their long dendritic arms through the space between cells into the lumen and snatch antigens |
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What happens after a Peyer's Patch takes up an antigen
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The lymphocytes activated by the antigen in the Peyer's patches proliferate locally, drain into the mesenteric lymph nodes and make their way into the bloodstream via the thoracic duct.
Activated B cells then home to the diffuse lymphoid tissues of the lamina propria (effector sites) both locally and at distant sites where they differentiate into plama cells and secrete IgA |
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True or False
The mucosal immune system is thought of as a separate immune system |
True
this is because mucosa-associated lymphoid cells mainly recirculate within mucosal tissue |
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What is the major effector molecule of the mucosal immune system?
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IgA
it provides the first line of defense at mucosal and epithelial surfaces IgA prevents attachment of viruses and bacteria to mucosal surfaces IgA in breast milk also provides important early protection from newly encountered bacteria to newborns |
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How does IgA provide the first line of defense
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Polymeric IgA is transported into the gut lumen through epithelial cells at the base of crypts
It binds to the mucus layer overlying the gut epithelium IgA in the gut then neutralizes pathogens and their toxins |
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2 subclasses of human IgA
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IgA1 - sensitive to certain bacterial proteases
IgA2 - resistant to bacterial proteases |
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Who produces IgA
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It is produced from B Cells initially activated in the inductive sites of the O-MALT
Once activated in Peyer's patches the B cells proliferate locally, begin to undergo isotype switching to IgA and migrate to the lamina propria via the blood stream In the lamina propria the B cells differentiate into IgA secreting plasma cells |
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Where are the principle sites of IgA synthesis
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the gut, respiratory tract, lactating breast and other exocrine glands such as the salivary and tear glands
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transcytosis
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a process by which IgA is transported across the epithelial barrier to the mucosal surface of the epithelium
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Poly-Immunoglobulin receptor
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attaches to DIMERIC IgA which was secreted by plasma cells.
Binding of DIMERIC IgA to this receptor induces its transcytosis across the epithelial cell to the mucous layer of the epithelial cell once it's released on the apical side it takes a small piece of the receptor called the secretory component which remains attached to the IgA |
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Atopic
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people with a predisposition for allergy
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Allergen
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an antigen (harmless in most people under most circumstances) that stimulates allergic response in atopic individuals
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Sensitization Vs Elicitation
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Hypersensitivity diseases require initial sensitizing exposure to an allergen, followed by a subsequent exposures that elicit symptoms
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Immune response Vs Immune Reaction
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most hypersensitivity diseases require sensitization involving and immune response that produces potentially harmful soluble or cellular factors
Immune reactions are elicited, damaging responses in response to these responses |
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4 Classifications of hypersensitivity (they are not mutually exclusive)
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Type - Immune Reactant...
I - Antigen specific IgE antibody. Mast cell, basophil, eosinophil degranulation involved with release of pharmacologically active agents II - Target tissue-specific IgG antibody. AB binding is specific for intrinsic or extrinsic cell-bound molecules and subsequent activation of complement cascade III - IgG antibody NOT specific for a target tissue. Associated with formation and deposition of antibody-antigen complexes in sensitive tissues and activation of complement cascade IV - T lymphocytes (CTL and/or TH1) and sometimes macrophages. Associated with effector T cells that destroy antigen-coated target cells either directly or indirectly by activating macrophages |
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Type I hypersensitivity example
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Allergic rhinitis
Allergic Asthma Venom reactions Food / Drug allergies Anaphylactic shock |
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Type II hypersensitivity example
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Drug-induced hemolytic anemia
blood transfusion reactions Hemolytic disease of the newborn (HDN) Autoimmune diseases involving autoreactive antibodies |
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Type III hypersensitivity example
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Serum sickness
Farmers lung syndrome Rheumatoid arthritis Systemic Lupus Erythematosus |
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Type IV hypersensitivity example
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Contact dermatitis (Poison Ivy, oak, metals)
TB skin test granuloma |
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Type I (Immediate) Hypersensitivity
SENSITIZTION ELICITATION |
Sensitization - Exposure to an allergen resulting in antigen-specific antibody production. Many possible routes of exposure
effective activators are TH2 molecules. They produce IL-4 which promotes selective switching to IgE antibody production During sensitization, allergen-specific IgE binds onto mast cells, basophils and eosinophils. These cells express FceRI Elicitation - the symptoms are caused by a released pharmacologically active factors that cause increased vascular permeability, increased blood flow, decreased blood pressure, increased mucus secretions and smooth muscle contraction. observed within minutes of exposure, dependent on cross-linking of allergen-specific IgE fixed onto mast cells or basophils |
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Degranulation
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the release of pharmacologically active mediators from the cytoplasmic granules of mast cells or basophils.
Begins when allergens are simultaneously bound to adjacent IgE molecules fixes to specialized Fce receptors on the surface of mast cells or basophils. Bridging between IgE molecules triggers an INFLUX OF CA++ which mediates a decreased production of Cyclic AMP this destabilizes the membrane, and arachidonic acid is produced. Leukotrienes and prostglandins are produces (which are both important lipid mediators) |
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What mediators are released in degranulation
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Histamine - increased vascular permeability and local blood flow
Leukotrienes and Prostglandins - cause smooth muscle contraction, increased vascular permeability and mucous secretion Chemokines - attract leukocytes Enzymes - that break down tissue matrix proteins Cytokines - promote inflammatory activities, amplification of TH2 responses and stimulate the growth and activities of eosinophils |
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Skin reactions to allergen
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Wheal and flare reactions are observed following local intracutaneous exposure to allergen like an insect bite
a more disseminated form of this reaction, often associated with allergen ingestion is Urticaria (Hives) |
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Gut reactions to allergen
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cramping, vomiting, diarrhea due to smooth muscle contraction
Urticaria (hives) if the allergen is systemic Anaphylaxis can also occur |
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Lung reactions to allergen
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Allergic rhinitis
more serious reactions occur following activation o fmast cells of the submucosa of the LOWER airways resulting in allergic asthma |
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Systemic reactions to allergens
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can be catastrophic if the exposure is significant
widespread vascular permeability, decreased blood pressure, contracted smooth muscles that can constrict airways this form of immediate hypersensitivity is referred to as SYSTEMIC ANAPHYLAXIS that may progress into the most sever form...ANAPHYLAXIS SHOCK |
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Late-Phase response to an allergen
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these occur in the hours after degranulation
Associated with the recruitment and activation of multiple cell tyupes, including inflammatory ganulocytes (which respond to chemokines released during degranulation) |
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Desensitization (treatment option)
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Goal is to shift IgE-dominated antibody response to IgG production (because IgG is much less effectively associated with mast cells)
administer multiple small, then escalated doses of allergen |
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Type II (Cytotoxic antibody) Hypersensitivity
SENSITIZTION ELICITATION |
Sensitization - production of antibodies reactive with extrinsic (foreign) antigens or reactive with intrinsic antigens produced by the target tissue itself.
Elicitation - Symptoms are usually caused by the binding of antigen-reactive antibody (usually IgG) SPECIFICALLY to antigen-coated host cells, follow by direct lysis due to complement activation and further aggravated by release of active by-products of teh complement cascade (ANAPHYLATOXINS, C5a, C3a) |
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Examples of Type II cytotoxic hypersensitivity
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Hemolytic disease of the newborn
Rh- mom with an Rh+ fetus. When baby is delivered mom is exposed to baby blood and antibodies are made against Rh since the mom is Rh- In a second pregnancy, these antibodies cross the placenta (IgG can cross placenta) causing severe anemia if the fetus is again Rh+ To fight this, RhoGam is administered and has been helpful in attempting to avoid these complications |
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Goodpasture's Syndrome
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a rare autoimmune disease in which antibodies attack the lungs and kidneys, leading to bleeding from the lungs and to kidney failure. It may quickly result in permanent lung and kidney damage, often leading to death. It is treated with immunosuppressant drugs
Caused by the production and binding of antibodies reactive with the basement membranes of renal glomeruli (and sometimes alveoli) The antibody specificity is for Type IV collagen of the basement membrane The antibody binding triggers the complement cascade, as well as the activation of monocytes and neutrophils via their Fc receptors |
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Type III Hypersensitivity (Immune complex disease)
Sensitization Elicitation |
Sensitization - initial antigen exposure results in activation of antigen-specific B Cells. Specific antibodies are reactive with antigen that is typically SOLUBLE AND FREELY CIRCULATING
Elicitation - many cross-linked antigen-antibody bonds are made. Results in large INSOLUBLE complexes. The amount or location exceeds what can be handled by phagocytes and they are deposited on nearby tissues The important thing to remember is that VOLUME not TYPE is what causes this. The specificity of the antibody involved is typically unrelated to antigens expressed by the tissue being attacked (Distinguishes Type II from this Type III) You can detect these depositions in biopsie. Activation of complement system, including both lytic activities and release of Anaphylatoxins (C5a and C3a), recruitment of neutrophils, basophils and eosinophils |
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Arthus Reaction
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basis for tests indicative of Type III hypersensitivity
inject an antigen into skin that attracts circulating IgG which forms immune complexes this activates complement cascade attracting phagocytic cells (C5a is prominent) and results in local inflammatory response |
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Serum Sickness
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a reaction to proteins in antiserum derived from a non-human animal source. It is a type of hypersensitivity, specifically immune complex hypersensitivity (type III)
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Type IV (Delayed-Cell mediated) Hypersensitivity
Sensitization Elicitation |
This is similar to cell-mediated responses to local infections
Sensitization - Activation of CD4+ TH1/TH17 cells is key to initiating type IV hypersensitivity. Typical T activation proceeds but the host tissue which the foreign antigen is attached is also targeted CD8+ cytotoxic T cells are activated because some antigens are lipid soluble and cross the membrane. Elicitation - this is an exaggerated form of cell-mediated immunity. distinguished from types I, II, III because antigen-specific T cells are used. Many symptoms are caused by T Cell derived cytokines like: 1) Chemokines 2) IFN-y 3) TNF-a and TNF-B 4) IL-3/GM-CSF The result of this heavy recruitment is the in turn recruitment of CD+ T cells that may not be antigen specific Overtime macrophages are the most prominent cell type |
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How are Type I and Type IV hypersensitivities different with regards to their tissue swelling?
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Type I hypersensitivity has swelling that is soft to the touch. Mainly because it is fluid build up
Type IV swelling is firm to the touch because of antigen expression/deposition |
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3 Variatns of Type IV hypersensitivity
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1) Contact Hypersensitivity - epidermal reaction with Langerhans' cell as the principle cell that presents antigens to T Cells. Infiltrating cells are almost exclusively CD4+ T Cells. 24-48 hours after exposure
Tuberculin Hypersensitivity - an intradermal reaction with macrophages being principle cell that presents antigen to T cell. CD4+ outnumber CD8+ T Cells by about 2:1 and occurs within 24-48 hours Granulomatous Hypersensitivity - occurs SLOWLY (21-28 days). inorganic materials can stimulate this, or difficult to degrade antigens. LACK OF PARTICIPATION OF LYMPHOCYTES Granuloma formation is the hallmark of this type of sensitivity. Macrophages form a huge cell with a "cuff" of T Cells around them. The size of the granuloma can cause tissue damage. Some bacterial agents can survive phagocytosis. Constant antigen presenting leads to the same granuloma result....think Tuberculosis! |
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Where is the lamina propria
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Under the epithelial layer
In the DMAL there are two compartments: epithelia and the lamina propria under it |
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What type of T cells in lamina propria
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CD4+ and CD8+
CD8+ are also in the epithelial layer of DMALT |
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How do pathogen-derived antigens at the mucosal surface gain access to the MALT
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M cells
Transfers from lumen of the gut to the T cell zone of the Peyer's Patch of into a lymphoid follicle also in the Peyer's Patch |
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L-selectin
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a molecule that helps naive lymphocytes enter tissues (specifically secondary lymphoid tissues).
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MadCAM-1
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captures lymphocytes in the bloodstream and draws them into the lamina propria
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What holds the IgA dimers together?
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The J chain (Don't confuse this with the VDJ segments)
J = join IgA isn't the only multimeric Ig. IgM is also another multimeric Ig J chain is produced by the B cell that links the IgA together Remember there are two subclasses of IgA = 1 & 2 IgA is produced by Plasma cells in the Lamina propria |
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How do T Cells enter the Peyers Patches
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from blood vessels directed by the homing receptors:
CCR7 and L-selectin |
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Which type of hypersensitivity is characterized by Antigen-Specific IgE
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Type 1
Result is release of pharmacologically active agents from IgE fixed mast cells and/or basophils Complement cascade is NOT PART of Type I |
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Which type of hypersensitivity is characterized by Tissue-specific IgG
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Type II
Result is activation of complement; damage to host |
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Which type of hypersensitivity is characterized by Non Specific IgG
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Type III
Result is deposition of Ab-Ag complexes in sensitive tissues and activation of complement cascade |
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Which type of hypersensitivity is characterized by T Cells/macrophages
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Type IV
Result is effector T Cells/macrophages destroy |
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Autoimmunity
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loss of regulation designed to prevent immune reactivity against the host's own antigens
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Central Tolerance
T CELLS |
The negative (PRIMARY, for eliminating self) and positive selection of T Cells in the Thymus
Should not recognize self but be very sensitive to foreign antigens Not a perfect mechanism though, and some self-reactive T Cells escape |
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Peripheral Tolerance
T CELLS |
mechanisms intended to tone-down "self" T Cells
2 mechanisms Anergy Suppressive Regulatory T Cells (Treg Cells) |
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AutoImmune Regulator (AIRE)
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transcriptional activator that allows epithelial cells in teh thymus to express numerous proteins that are usually restricted to expression by particular tissues out in the body
This allows for a broader effect of negative selection If this wasn't allowed, T Cells would be negatively selected only for self-cells located in the Thymus... but you need them to be systemically self-recognizing.. |
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2 Opportunities for things to go wrong with regards to T CELL CENTRAL TOLERANCE
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1) The spectrum of self-peptides available in the thymus is not broad enough to guarantee that all T Cells against self are eliminated
2) MHC may not present certain self-peptides effectively for negative selection Relative Risk is a numerical value that is assigned between the risk of getting a disease and carrying a certain gene. Risk ≠ Certainty MHC alleles are the cause of number 2 |
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Immunologically Privileged Sites
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during early embryological development certain self-antigens in immunologically privileged sites (like the CNS) are sequestered. This keeps them from the T Cells
Part of the Peripheral Tolerance of T Cells If there is injury that disturbs the sequestering, there will be an autoimmune reaction |
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Restricted Distribution of Class II MHC
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This is part of peripheral tolerance of T Cells
The autoimmune responses of TH1, TH17, TH2 are limited by the restricted distribution of Class II MHC If MHC are inappropriately expressed, there is a greater chance for autoimmune response |
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Anergy Dependent on restricted distribution of co-stimulatory molecules
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Part of peripheral tolerance of T Cells
Many T Cells that are self-recognizing that escape the thymus will find many host tissues expressing MHC I (since it is distributed on virtually all cells/tissues) But most cells except for professional APCs can't give the 2nd signal. So the T Cells bind to the self-antigen and get signal 1 but not signal 2 either apoptosis or anergy (state of unresponsiveness) results |
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Regulatory (Suppressive) T Cells
(Treg) |
Part of peripheral tolerance of T Cells
A small subset of CD4+, CD25 T Cells regulate the balance of cytokines who are responsible for steering the inflammatory and autoimmune responses away from harmful effector activities Treg cells require 1) direct contact with their target T cells 2) Constitutively express a costimulatory molecule other than CD28 known as CTLA-4 |
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CTLA-4
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a costimulatory molecule expressed on Treg cells
Competes for the CD80/86 (B7) on the APC used in Treg cells in the peripheral tolerance of T Cells |
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Cryptic Epitopes
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weakly immunogenic regions of a protein due to inefficient presentation to T Cells
They may not initially activate T cells. but repeated presentation may allow these epitopes to become prominent later in the immune response |
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Central Tolerance
B CELLS where can things go wrong |
Clonal deletion of immature (IgM ONLY) B Cells occurs in bone marrow via negative selection during the sensitive immature B cell stage of development
3 opportunities for things to go wrong: 1) Incomplete clonal deletion of self-reactive B cells due to limited availability of self antigens in marrow 2) Somatic mutations may occur in B Cells activated to foreign antigen. This allows expression of receptors for antigen with new reactivities against the self in the periphery 3) Antigen Mimicry - structural similarity between foreign antigen and self antigen. Allows IMMUNE CROSS REACTIVITY example: Sterptococcal M protein antibodies cross react with structural proteins in heart valves. This causes Rheumatic Fever/Rheumatic Heart Disease |
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Peripheral Tolerance
B CELLS |
this is required to regulate the activities of self-rective B cells that escape Central Tolerance in the bone marrow
several mechanisms |
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Immunologically Privileged Sites
B CELLS |
This is part of peripheral tolerance of B Cells
Same as for T Cell privileged sites. Some autoimmune B Cell responses are limited by sequestering, during early embryological development, some self antigens in immunologically privileged sites (ie CNS) Trauma can damage this sequestering and an immune response results |
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Split Tolerance
B Cells |
A type of peripheral B Cell tolerance
B Cells who have escaped central tolerance are kept quiet due to the absence (via clonal deletion or anergy) of helper T Cells needed for their activation 2 cell types needed for a response, one is tolerant the other is not, but it is dependent on the first. NET RESULT = NO RESPONSE there is however a t cell bypass mechanism...on another slide |
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T Cell bypass mechanism
2 of them |
In peripheral B Cell tolerance there is something called split tolerance. This is when you need a T Helper Cell to activate an escaped B Cell
If no T helper Cell exists or is anergic then the B Cell won't be pathologically activated. However, 2 bypass mechanisms exist 1) Nonspecific, T inducer-independent induction of effector function Mitogens; certain products derived from infectious agents. (polyclonal B lymphocyte activators). When exposed to a mitogen, polyclonal B cell proliferation and differentiation will occur, regardless of antigen specificity of the b cell's antigen receptor (even if self-reactive) 2) Nonspecific, inducer-dependent - Physical linkage of a self antigen with a newly acquired, extrinsic (foreign) antigen. This is the result of linked recognition and activation of B cells with reactivity against the self antigen |
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Are autoimmune disease more common in men or women
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More common in women by a factor of 3-10X
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Grave's Disease
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Mechanism - autoantibody that acts as a TSH receptor AGONIST. Abnormally high levels of T3/T4
Presentation - Enlarged, nontender thyroid. Hyperthyroidism and metabolic imbalance may result in tachycardia, hypertension, diarrhea, muscle weakness. Insomnia and weight loss common. Irritability, tremors, sweating, heat intolerance. Basically the antibody acts like TSH |
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Myasthenia Gravis
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Mechanism - Antibody acts as acetylcholine receptor ANTAGONIST. Inhibits neuromuscular transmission do to impaired/destroyed receptor
Presentation - Weakness and rapid onset fatigue. Often ocular muscles are early affected. Diplopia, ptosis is often symmetrical. Slurred speech and difficulty swallowing are also early signs. Large limb and trunk muscles may be affected next |
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Type 1 Diabetes Mellitus
(Insulin dependent) |
Mechanism - TH1 and CD8 autoreactive T Cells and antibody with reactivity against insulin-producting pancreatic Beta Cells (and sometimes insulin itself)
Presentation - Typical presentation includes fatigue, increased thirst, polyuria and weight loss |
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Multiple Sclerosis
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Mechanism - Demyelinating disease of the CNS. Inductive event is unknown; mixed and complex immune effectors
Probably involves Type II and Type IV hypersensitivity, but the exact antigen target is unclear. Both myelin and myelin-producing cells (oligos/Schwans) are damaged. Presentation - fatigue, numbness (hypoesthesia), tingling, muscle weakness or spasms. Ataxia, problems with speech (dysarthria), dysphagia and bowel control. Depression, unstable mood also common |
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Rheumatoid Arthritis
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Mechanism - mixed antibody and CMI effectors involving Type III and Type IV hypersensitivites. Prominent imune complex disease in joints
Presentation - inflammation in affected joints, especially after prolonged inactivity. RF = Rheumatoid Factor. It is an abnormal IgG antibody. An antibody response is generated for this antibody and the immune response kicks off. In time the complement cascade is started. Progressive tissue damage in the joint |
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Systemic Lupus Erythematosus
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Mechanism - autoimmune attack with a single antigenic stimulus is VERY UNLIKELY. it is probably a complex immunoregulatory impairment. Sex hormone influences are likely to be important (greater in women than in men)
Type II hypersensitivities are observed, but Type III are responsible for much of the life-threatening pathology. Numerous circulating engorged phagocytic cells (Lupus Erythematosus [LE]) can be observed attempting to clear immune complexes Presentation - no typical presentation. Any organ/tissue can be affected. Most common in women of child-bearing age. fever, rash, malaise, joint pains, myalgia, fatigue... Periods of remission and unpredictable flare-ups |
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Some Immunopathological consequences in SLE
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Systemic Lupus Erythematosus
Autoantibody Reactivities / Pathological Consequences Erythrocytes / Hemolytic anemia Platelets / Thrombocytopenia Coagulants / clotting problems Lymphocytes / Lymphopenia, immune deficiencies Neutrophils / Neutropenia, phagocyte deficiencies Neuron / CNS dysfunction Any of the above reactivities plus: DNA, nucleoproteins, IgG / Severe immune complex disease, renal disease |
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Goodpasture's Syndrome
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This is a Type II Hypersensitivity
Mechanism - autoantibodies against Type IV collagen of basement membrane, primarily react with renal glomeruli but can also react with pulmonary alveoli Presentation - vague early symptoms such as fatigue, nausea, burning upon urination or difficulty breathing. vague early symptoms and rapid progression of the disease. Diagnosis usually not until later stages. Demonstration of circulating antibodies against Type IV collagen may aid the diagnosis, or kidney biopsy |
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Acute Idiopathic Polyneuritis
(Guilliam-Barre syndrome) |
Organ affected - Peripheral nerves
Pathological Manifestations - Demyelination Sort of like MS |
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Hashimoto's thyroiditis
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Thyroid is affected
Anti-thyroglobulin; anti-thyroid epithelium |
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Addison's disease
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Adrenal glands are affected
anti-adrenal cell membranes and lymphocyte/monocyte cortical infiltration |
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Sjorgren's Syndrome
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Salivary glands are affected
Glandular inflammation |
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Autoimmune hemolytic anemia
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Erythrocytes affected
Erythrocyte destruction and anemia |
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Thrombocytopenias
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Platelets or megakaryocytes affected
Platelet destruction, abnormal bleeding |
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Chronic atrophic gastritis
aka pernicious anemia |
gastric mucosa affected
Loss of gastric secretory function. Failure of cobalamin (Vitamin B12) to absorb due to loss of intrinsic factor or the cells that produce it. |
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Intestinal granulomatous disease
aka Crohn's disease |
Mucosal membrane of terminal ileum affected
Mucosal ulceration, obstructive granuloma |
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Rheymatic fever
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Heart is affected
myocarditis, scarring of heart valves |
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Pemphigus vulgaris
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epidermis is affected
blistering of the skin |
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What must be present for an autoimmune disease to present
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An inductive event - often we don't know what it is
Often a genetic predisposition - often related to MHC, Gender and other unknown factors Effective Collaboration - APCs, Helper T Cells, B Cells |
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True or False
The longer the time of infection the more likely it is that class switching will occur |
True
Example: In rheumatic heart disease after prolonged infection IgG will predominate from IgA class switching IgA is good against cell wall of Streptococcus but also react with myocardium and joints |
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Why should you always treat strep throat
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Antibiotics should be used when children get strep. Untreated strep can cause rheumatic fever which can cause damage to the heart valves - which could be problematic in later years.
The incidence of rheumatic fever has greatly diminished since streptococcal infections began to be treated with antibiotics. |
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What hypersensitivity is Rheumatoid Arthritis
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Type III hypersensitivity
C Reactive Protein is important in inflammation Abnormal IgG in joints promotes and immune response. Anti-IgG AB that is generated against abnormal IgG is called RHEUMATOID FACTOR Creates insoluble Ag/Ab complexes --> complement cascade --> joint damage --> rheumatoid arthritis |
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RBC sedimentation rate is indicative of what
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raised levels are indicative of inflammation.
a very handy test for inflammation |
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What is Rheumatoid factor
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an antibody that reacts with IgG
it causes an immune complex to form and can cause rheumatoid arthritis FROM WIKIPEDIA (RF) is the autoantibody (antibody directed against an organism's own tissues) that is most relevant in rheumatoid arthritis. It is defined as an antibody against the Fc portion of IgG. RF and IgG join to form immune complexes that contribute to the disease process. Very frequently Lupus patients will be positive for RF |
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Does Rheumatoid Factor only point towards Rheumatoid arthritis?
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No
Lupus (SLE) patients often also have elevated RF levels |
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Anti-nuclear antibodies (ANA)
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are autoantibodies directed against contents of the cell nucleus
They are present in higher than normal numbers in autoimmune disease. The ANA test measures the pattern and amount of autoantibody which can attack the body's tissues as if they were foreign material. Test is often by immune fluorescence |
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LE Cells
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Lupus Erythematosus
Massive macrophages that are packed full of the immune complexes formed in Lupus They can't handle all the stuff they eat and sometimes it just pushes the nuclei out |
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When you have tissue damage in Type III hypersensitivity. What process causes most of the tissue damage?
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the complement cascade "an explosion"
a huge amount of antigen-antibody complexes form, deposit and cause a complement explosion |
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Why in Lupus can Complement C3 and C4 levels be low?
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low complement levels in lupus usually mean increased disease activity.
When the body uses the complement system to clear immune complexes from the blood it results in low complement levels. The complement proteins are not produced as quickly as they are being used. |
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Anaphylatoxin
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fragments (C3a, C4a and C5a) that are produced as part of the activation of the complement system.
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What type of hypersensitivity is Lupus
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Type II (probably the first to show up)
Type III Maybe some type IV |
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What type of hypersensitivity is MS
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Type II
Type IV - cell mediated |
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10 Warning Signs of Primary Immunodeficiency
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>8 Acute Otitis Media / yr
>2 Serious sinusitis / yr >1 month on antibiotics W/ no effect >1 pneumonia / yr Failure To Thrive Recurrent abscesses Persistent thrush or candidiasis Need IV antibiotics >1 deep-seated infection (meningitis, osteomyelitis, cellulitis, sepsis) + Family History |
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Multiple Myeloma
(Myeloma aka plasmacytoma) |
this is when a malignant monoclonal transformation of a plasma cell occurs
unregulated growth, primarily in bone marrow and they secrete the antibody for which they're programmed to make in huge levels Thought to occur (in some cases) by genes that regulate growth being inserted into the highly variable region that is transcribed frequently. The locus (most common) is 14q32 translocation |
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How do monoclonal plasma cells which are overgrowing (malignancy) cause anemia?
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They overgrow the hematopoietic activites so there are less red blood cells
Palor, weakness, fatigue are common. If it affects thrombocytes then thrombocytopenia results with accompanied bruising, bleeding If leukocytes are affected then leukopenia results and patient is immunocompromised and susceptible to infection |
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Stem Cells --> Myeloid Lineage Cells --> ????
HEMATOPOIESIS |
Granulocytes
Monocytes |
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Stem Cells --> Megakaryocyte --> ???
HEMATOPOIESIS |
Platelets
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Stem Cells --> Erythroid Lineage --> ???
HEMATOPOIESIS |
Red Blood Cells
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Stem Cells --> Lymphoid Lineage --> ???
HEMATOPOIESIS |
B & T Lymphocytes
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Myeloma Cells can impede the activities of what
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hematopoiesis
osteoblast / osteoclast activities - Typically osteoclast activity is increased while osteoblast activity is diminished. WEAKENING OF BONES RESULTS. Measure this by measuring blood Ca++ levels This is because they grow so much that they take all the space required for other activities |
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Immunonephelometry
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Very rapid (~2 hours for results), direct and fully automated method. Technique of choice for measuring the amount of IgG, IgA and IgM in the blood
Sensitivity is ~same as ELISA, fluorescence, radial immunodiffusion Principle is that immune complexes will form by the reaction of patient serum Ab with standardized anti-an A beam of incident light is passed through the mixture (in a nephelometer - measures particles in suspension) The amount of scattered light increases as a function of increased amount of antibody-anti-ab complexes formed. |
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Serum Protein Electrophoresis (SPE)
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separates 5 major fractions of serum based on their ELECTROPHORETIC MOBILITY
This is their rate of movement as they move through an electric field. They move TOWARDS a POSITIVE electrode (since they're inherently negative) Therefore the proteins with highest negative charge move furthest. In order of farthest-lowest movement: Albumin, alpha1 globulins, alpha 2 globulins, beta globulins, gamma globulins Each fraction above has a family of components associated with it. except for Albumin which is only Albumine. ex: gamma globulins = IgG, IgA, IgM while; Beta Globulins = IgA, IgM, lipoprotein and transferrin This test is useful in determining pathological conditions associated with any of the 5 serum fractions: hypogammaglobulinemia, hypergammaglobulinemia etc Can be done on serum, concentrated urine, or concentrated CSF |
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Idiotype
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a unique serologically defined region roughly corresponding to the antigen-combining sire
each antibody and its B Cell of origin, has one unique antigen binding site, and therefore one unique idiotype |
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Immunofixation Electrophoresis (IFE)
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Used to detect the presence of a particular immunoglobulin isotype in serum, urine, and CSF
In multiple myeloma often light chains are over produced (more than heavy chains) So they enter the blood in the form of light chain dimers. These are filtered by the glomeruli and are called Bence-Jones Protein, subequently they can be found in the urine. IFE can find both heavy-chain class & light chain type in the serum, as well as Bench Jones protein in the urine. Fast (~2 hours), First serum proteins are separated by electrophoresis. Then a cellulose acetate strip soaked with the Ab against a particular serum component are placed on top of the gel. The Ab's leave the strip and cause the serum Ab's to "fix" in the gel. Then visualized by staining |
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Syngeneic
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identical genetic constitution
ex: identical twins |
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Allogeneic
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Differing genetic constitution between members of the same species
ex: humans who aren't identical twins |
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Xenogeneic
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Major genetic differences between different species
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Autograft
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Tissue grafted back onto the original donor
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Isograft
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tissue grafted between syngeneic individuals
ex: between identical twins |
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Allograft
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tissue grafted between allogeneic individuals
Ex: from one person to another person (not identical twin) |
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Xenograft
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Tissue grafted between xenogeneic individuals
ex: ape to man |
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What are the targets of transplant rejection
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Major Histocompatibility Complexes (MHC)
closely linked family of polymorphic genes which encode for cell surface Histocompatibility Antigens that are the targets of transplant rejection reactions |
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Allograft Rejection & Timeline
AKA Host-Versus-Graft-Rejection |
Example is skin graft rejection (between two unrelated people of same species)
Day 2-4 graft is pale, then vascularized and pink. Looks promising but problems are brewing Day 4-7 Graft becomes cyanotic and necrotic as destruction phase has commenced. Perivascular infiltration by mononuclear cells and vascular thrombosis Day 10-12 Macroscopic signs of rejection become obvious and graft falls off |
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What determines the kinetics of graft rejection
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Genetic Difference
Quantity of tissue engrafted Type of tissue engrafted Immune status of recipient Previous exposure to graft With no previous exposure, FIRST SET REJECTION KINETICS are anticipated (10-12 days rejection). If there has been previous exposure, SECOND SET REJECTION KINETICS is anticipated. |
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3 Phases of Allograft Rejection
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Recognition Phase
After transplantation, graft antigens shed from the graft and are taken up, processed and displayed on APCs. Antigen-reactive Lymphocytes primarily in draining lymph nodes are activated. Some bloodborne lymphocytes are activated too as vascularization occurs. Early immune recognition of the graft is PRIMARILY BY CD4+ Cells (T helper/inducer and inflammatory) Proliferation and Differentiation Phase Following contact with antigen, CD4+ T cells (and/or macrophages) in regional draining lymph nodes mediate the induction of proliferation and differentiation of effector cell precursors (T and B cells) Effector T Cells leave the lymph node and reach the graft via blood vessels Destruction Phase Activated CYTOTOXIC CD8+ T LYMPHOCYTES (CTL) are the primary destructive forces in the rejection process. Although CD4+ help some, and B antibodies also play a role, CTL are able to directly lyse engrafted cells and release various toxic and chemotactic factors |
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What is the 2nd signal for Cytotoxic T Cells to activate
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Recall the 1st signal is binding of T Cell receptor to the antigen-APC complex
2nd Signal is the co-stimulatory signal between CD28 (on T Cell) and B7 (on APC) The T Cell can perform its function without B7 but only if it has already been activated by B7 |
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Cytolysis of Graft Cells
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Cytoplasmic granules in CTL move to points adjacent to target cell contact
The granules contain PERFORINS that are capable of intercalating and polymerizing in the target cell membrane to form disruptive channels The induction of GRANZYME expression/release (which is though to have serine protease activity) enters the target cell and engages the caspase pathway to trigger Apoptosis FAS/FAS LIGAND interaction may also play a role in triggering apoptosis |
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Activated B Cell role in graft rejection
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They differentiate into Ab-secreting plasma cells. Anti-graft Ab's may result in:
1) Complement mediated lysis 2) Activation of chemoattractant complement components (C5a) that attracts PMNs who in turn cause graft destruction by proteolytic enzymes and vasoactive peptides which enhance the invasion of monocytes and other PMNs 3) Antibody-Dependent Cell-mediated Cytotoxicity (ADCC). This is through K/NK cells |
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Strategies to avoid graft rejection
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Tissue Matching - identifying and matching of cell surface antigens (mostly HLA...MHC) molecules expressed by the donor and recipient tissues
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What are primary targets of CTL (cytotoxic T Cells) in graft responses
What are the primary targets of CD4+ helper cells in graft responses |
Class I Antigens (HLA-A, B, C) are primary CTL (CD8+) targets. recall HLA codes MHC...
Class II Antigens (HLA-DP, DQ, DR) are the primary targets of CD4+ T Helper Cells |
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Tissue-Typing
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Determination of exact collection of HLA antigens expressed by a graft donor/recipient.
performed with panels of monoclonal antibodies reactive with individual HLA antigens alternative PCR techniques can be used to identify HLA antigens at the gene level |
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Is there a relationship between graft-host matching of HL/A genes and the immune response
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No
Major discrepancies can lead to minimal responses and vice versa. Even perfect matches are sometimes rejected. Thus sometimes a functional test of graft compatibility is needed. |
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Mixed Leukocyte Culture (MLC) Test
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This mimics proliferation phase of graft rejection by measuring stimulation of recipient CD4+ T Cells against allogenic donor cells
Primarily the targets are Class II (HLA-D) alloantigens found mainly on B Cells or macrophages. |
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Mixed Leukocyte Culture (MLC) Test PROTOCOL
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1) obtain cells from potential graft recipient to be tested for alloreactivity (aka Responder Cells) and get cells from a potential donor (aka Stimulator Cells)
2) Stimulator Cells receive a lethal dose of irradiation or mitomycin C (a DNA synthesis inhibitor) so that PROLIFERATIVE ACTIVITY IS ONLY TO RESPONDERS (One-Way-MLC) 3) Mix and culture stimulator and responder cells. Incubate for a few days. a radioactive isotope of DNA precursor is added. This then measures rate of cell division/proliferation 4) Calculate the STIMULATION INDEX (SI). Counts Per Minute (CPM). The higher the number the more proliferation and thus the less attractive that donor-recipient combination becomes |
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How is immunosuppression used to prevent graft rejection
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Radiation
Cytotoxic Chemotherapy But there is an increased susceptibility to infection. |
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Graft Versus Host Disease (GVHD)
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This is when hematopoietic elements from the donor (mature T Cells and monocytes mostly) are transferred into the recipient.
Immune responsiveness of the donor is generated against MHC differences expressed by the RECIPIENT. Happens most when immunocompetent donor lymphoid cells are transferred into an immunoINcompetent recipient ex: newborns, immunosuppressed adults, immunodeficient patient |
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Chronic Graft Versus Host Disease (GVHD) symptoms
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Generally becomes apparent after more than 3 months post transplant and affects a wide range of organs
Skin, Liver, Gut involvements are common. Produce symptoms of Rash, Jaundice and Diarrhea. |
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Why do we do bone marrow / stem cell transplants
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It is a therapeutic strategy useful for replacing hematopoietic elements that are damaged or missing due to immunopathologic disease or immunoablative therapies
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Hematopoiesis
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Differentiation and development of cells of the blood system originating from a common, self-renewing multipotential progenitor (STEM CELL)
Stem Cell = CD34+ cells A rich source is bone marrow of adult, but also at low frequency in the blood. Each blood cell is derived from stem cells by unique programs of cytokine-driven DIFFERENTIATION that dictate which genes are "on" or "off" |
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HSCT
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Hematopoietic Stem Cell Transplant
Can be taken from: 1) Bone marrow 2) Blood 3) Umbilical Cord Blood |
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why perform a hematopoietic stem cell transplant?
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1) To replace abnormal/defective bone marrow stem cells
ex: aplastic anemia, a disease in which hematopoietic stem cells are abnormal or ate the target of an autoimmune process 2) To treat diseases in which the transplanted stem cell can replace the immune system e: SCID therapy 3) Treatment of inborn errors of metabolism ex: Hurler's Syndrome 4) Treatment of cancer ex: hematologic malignancies & solid tumors |
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What determines compatibility for stem cell transplant
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Ideal donor is a compatible sibling
To be compatible, the patient and recipient need to share the same HLA antigens or "HLA-Type" HLA = Human Leukocyte Antigen (is the human version of MHC) For siblings to be compatible they must inherit the same haplotype from mom & dad |
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Autologous transplants are used exclusively to treat what
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Cancer
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Potential donors of Hematopoietic stem cells
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HLA-compatible siblings
HLA-compatible relative (rare) Matched unrelated donors (banks) Umbilical cord blood Autologous |
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Why does HSCT allow for high doses of chemo/radiation and why is that helpful
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high doses of chemo/radiation have better cure rates/better tumor control rates.
But a limitation of high dose is that it suppresses bone marrow creating periods of low blood counts If high-doses are delivered there is a risk that the patient may never recover their blood count and die to bleeding/infection HSCT shortens the period of low blood count (pancytopenia) allowing higher doses to be administered |
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Graft Versus Tumor Effect
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Even with HLA typing, some patients who undergo allogenic HSCT have multiple minor antigen disparities with the donor
Immunological reaction begins of the transplanted cells against the recipient's tumor cells This can be good for tumor control or eradication in addition to the tumoricidal effect of high doses of chemo / radiation |
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Malignant Diseases treated with HSCT
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Acute leukemia
Chronic leukemia Hodgkin Lymphoma Non-Hodgkin Lymphoma Multiple Myeloma |
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Complications of HSCT
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Infections (Early = during neutropenic period, gram negative bacteria from the gut. Intermediate = after engraftment but early after could be fungal, viral. Late = after 3 monts could be incomplete immune reconstitution or GVHD)
Bleeding Mucositis Nausea and Vomiting Hair Loss GVHD Pulmonary hemorrhage or fibrosis Cardiovascular pericarditis Endocrine (hypothyroidism, infertility) |
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Acute GVHD
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seen in first 3 months after transplant. Involves 3 main organs:
skin liver GI Tract Skin involvement can vary from a faint rash to skin denudation (wearing away) and bullae (blisters) Severe diarrhea and liver failure carry high mortality |
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Chronic GVHD
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seen after 3 months post-transplant
resembles more like a chronic autoimmune disease with manifestations such as: skin thickening oral ulcers esophageal strictures joint contractures pulmonary dysfunction |
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What percentage of patients who get transplant have GVHD
what is the best treatment |
30-70% in all transplant patients
Prevention is the best treatment, since corticosteroids and second line therapies only have variable success |
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What 3 things must be considered for transplant
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Patient - must be able to tolerate the trasplant (good organ function), good heart/lung function
Disease - must be a reasonable chance for cure. High morbidity and significant mortality Transplant-related factors - is there high involvement of tumor in bone marrow or blood? can autologous transplant cure disease? tolerate high doses of chemo / rads? |
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2 main mechanisms for eradicating tumors with HSCT
anything new? |
1) Delivery of high dose chemo / rads before transplantation
2) GVT (graft versus tumor) effect However, a new approach 3) Non-myeloablative or "reduced-intensity" have been used recently on elderly patients. Lower doses of chemo/rads are used with the hopes that GVT will do the rest of the work. Fairly successful so far |
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Serum Protein Electrophoresis, which peak is closest to the anode (positive)
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Albumin, it is also the largest and sharpest peak
Closest to the anode because it is most negative Always orient yourself to albumin, Peaks that follow are: α1, α2, β, γ |
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In Serum Protein Electrophoresis, what is found in the following regions:
1) α1 2) α2 3) β 4) γ |
1) α1 - Orosomucoid and antitrypsin migrate together but orosmucoid stains poorly so alpha 1 antitrypsin (AAT) constitutes most of the alpha-1 band. Decreased in nephrotic syndrome, emphysema
2) α2 - his zone consists principally of alpha-2 macroglobulin (AMG) and haptoglobin. There are typically low levels in haemolytic anaemia 3) β - Transferrin and beta lipoprotein (LDL) comprises the beta-1. Increased beta-1 protein due to the increased level of free transferrin is typical of iron deficiency anemia, pregnancy, and oestrogen therapy. Increased beta-1 protein due to LDL elevation occurs in hypercholesterolemia. Beta-2 comprises C3 (Complement protein 3). It is raised in the acute phase response. Depression of C3 occurs in autoimmune disorders as the complement system is activated and the C3 becomes bound to immune complexes and removed from plasma. 4) γ - The immunoglobulins (IgA, IgM, IgG, IgE and IgD) are the only proteins present in the normal gamma region, but note that immunoglobulins may be found in the alpha and beta zones. If the gamma zone shows an increase (or spike), the first step in interpreting the graph is to establish if the region is narrow or wide. If it is elevated it could be elevated in a single narrow "spike-like" manner indicating monoclonal gammopathy or a broad "swell-like" manner (wide) indicating polyclonal gammopathy. |
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Idiotype
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unique SEROLOGICALLY DEFINED region on an antibody. It's shared characteristic between a group of immunoglobulin or T cell receptor (TCR) molecules based upon the antigen binding specificity and therefore structure of their variable region.
This is in the CDR regions (complementarity Determining Regions**) |
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Complementarity Determining Regions
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regions within antibodies (also known as immunoglobulins) or T cell receptors where these proteins complement an antigen's shape. Thus, CDRs determine the protein's affinity and specificity for specific antigens. The CDRs are the most variable part of the molecule, and contribute to the diversity of these molecules, allowing the antibody and the T cell receptor to recognize a vast repertoire of antigens.
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γ globulin
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A series of immunoglobulins (and others) in SPE.
Don't confuse γ globulin with IgG, it is in fact all immunoglobulins |
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True or False
Only 1 light chain gene can be expressed in one cell |
True
It will either be all Kappa or all Gamma |
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What chromosome are HLA genes on
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HLA = Human Leukocyte antigen, which is the human version of MHC (major histocompatibility complex)
Encoded on chromosome 6 |
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True or False
CD3 is carried on T Cells |
True
All T Cells carry it |
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What T Cells carry CD4
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TH1, TH4, TH17
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Imagine there are tumor cells in the blood, is it possible to find lymphocytes against it in one lymph tissue and not another....why
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Yes, chemokines will attract it to the area, but the adhesion molecules are what allows the lymphocytes to stay.
It is dependent on where these adhesion molecules are expressed. |
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Stimulation Index
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A number that represents:
If you mix donor and recipient tissues liklihood of bad thigns??? *** above 7 is bad? |
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What does a stimulation index of 1 mean?
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The response of the cells of recipient of cells of donor is 1 fold times the background (normal)
Thus 1 is a great stimulation index |
