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52 Cards in this Set
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Type III Hypersensitivity:
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Ag-Ab complexes, tissue damage from causing inflamm at deposition site
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Process of Type III Hypersensitivity:
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Sensitization of immune syst -> produce Abs -> complexes form (Ag-Ab) in circulation -> complexes deposited in tissue (often vessel walls or extravasc. sites) -> complement activation -> attract PMNs and macroph -> Focal acute inflamm and tissue destruction
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2 forms of Type III hypersens:
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Systemic (serum sickness, SLE, drug reactions): complexes form in circulation and deposit in many locations
Local (Arthus rxn, vasculitis, glomerulonephritis, arthritis, pneumonitis): complexes localized to one tissue or organ |
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Systemic Type III
Classic example: |
Serum sickness:
Ag begins to fall as complexes begin to rise -> complement begins to rise as complexes are deposited in tissues -> Free antibody begins to rise as all Ag is bound in complexes ---> Vasculitis, glomerulonephritis or C3a and C5a cause leaky vessels (caps) and smooth muscle contraction (bronchiole) |
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Localized Type III
Classic example: |
Arthus reaction: local tissue necrosis due to immune complex vasculitis
can be created experimentally via intracutaneous injection of Ag, binds to preformed Ab, forms local immune complexes, precipitate into vessel walls, trigger inflamm reaction |
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Localized Type III
Poststreptococcal Glomerulonephritis (PSGN): |
Post strep A infection, strep cell wall Ag's can bind to glomerular BM
Histology: "lumpy bumpy pattern" indicates type III (complex deposition), Lots of PMNs and fluorescent labelling doesn't show entire glomerular outline (it's splotchy) |
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Localized Type III
Vasculitis: |
tissue damage determined by where complexes are deposited
Involvement of small arteries often due to drugs B cells produce Ab -> Abs find Ag to bind to -> forms small complexes -> localize to BV wall -> attract PMNs and activate complement -> attack vessel wall -> hemorrhage/leakage -> purpura/infarct histology - complexes in muscle layer, lumen is gone (sticky thrombosis), eventually necrotic muscle wall, thrombosed lumen with PMN debris |
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Type IV Hypersensitivity:
types: |
attack by Ag-specific sensitized T cells and macrophages -> tissue damage
DTH - Delayed-Type Hypersensitivity (Th cells) Direct cell cytotoxicity (Tc cells) |
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Major effector cell in type IV:
Cell Products: |
macrophage-monocyte
Detrimental: TNFa/B, IL-1, superoxides, nitric oxide, hydroxyl radicals, neuron toxins Beneficial: TGFB, growth and trophic factors, GM-CSF |
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DTH
Examples: Essential Cells: Pathogenesis: of Tuberculin of Granuloma |
Tuberculin reaction, granulomatous reaction
T cells (especially Th1 and its cytokines), Ag presenting cells, macrophages Tuberculin: purified protein derivative injected -> reaction of sensitized lymphos with Ag -> release of cytokines -> attract unsensitized lymphos -> mononuclear cells accumulate around small veins and veinules (perivascular "cuffing) -> increased microvasc perm (endothelial cells change with inflamm, cells hypertrophy, leaky, like HEVs in lymph nodes, very sticky for circulating lymphos) -> interstitial plasma proteins, dermal edema and fibrin deposition -> induration Granuloma: Th cells replaced by macrophages -> macroph transform to epithelioid cells (like epithelia) and are surrounded by lymphocytes = granuloma -> persists -> causes tissue damage and scarring |
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Tc:
Preformed mediators: |
important in graft rejection and viral infection resistance, tumor immunity, express Fas Ligand which induces apoptosis when bound to Fas
perforin (create pores) and granzymes (through perforin pores into cell, activate caspases -> apoptosis) |
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Allograft rejection:
cells involved: hypersens involved: importance of HLA: |
Cd4, CD8, B cells/Abs
Types II-IV (not I) HLA/MHC system is highly polymorphic, almost always different (except identical twins), > HLA proteins recognized as foreign -> immune response and graft rejection |
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2 paths of rejection:
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1) Direct: (may be more important for acute rejection) APC from graft presents to CD4 and CD8 cells -> CD4 activates macroph and B cells -> CD8 cells recognize MHC I Ag and directly kill graft cells
2) Indirect: (may be more important for chronic rejection) APC from recipient, activates CD4, but CD8 can't kill or recognize graft because it was presented by self (??) |
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3 Rejection Reactions:
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based on timing, mechanism and morphology
hyperacute, acute, chronic |
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Hyperacute Graft Rejection:
gross appearance: pathology: |
moments to 14 hrs
involves preformed Ab's (previous implant, blood transfusion, birth - exposure to father's genome) Ag-Ab rxn at endothelium (vessel wall) Rapid vessel thrombotic occlusion, infarction, tissue necrosis Gross - cyanotic, mottled and flaccid path - thrombosed, dead tissue |
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Acute Graft Rejection:
Two types: |
weeks to months
two types may occur separately or together Acute Cellular: most common, sensitized CD4 and CD8 cells, lymphocyte/macrophage infiltrates, CD8 may damage endothelial cells (endothelitis) Acute Humoral: "rejection vasculitis", antigraft antibodies, vasculitis, thrombosis (may lead to lesions causing necrosis), endothelial proliferation (probably growth induced by cytokines), PMN and massive T cell infiltrate, foamy macroph |
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Chronic Graft Rejection:
pathology: Graft atherosclerosis: |
months to years
interstitial and intimal fibrosis (scarring) and mononuclear infiltrate, plasma cells, T cells, numerous eosinophils, organ atrophy, chronic vasculitis, obliteration of vessel lumen due to intimal proliferation and fibrosis intimal thickening, accum of SM cells and CT (not really atherosclerosis) |
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GVH disease:
Types: |
Graft vs Host: appears after BM transplant, immune cells of transplant attack host cells
Skin, Liver, GI most affected Acute: onset up to 100 days -> involves skin, liver, GI -> destruction of epithelium -> mild inflamm response Chronic: after 100 d -> many organs involved -> epithelial and mesenchymal lesions -> often large inflamm response |
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Process of Autoimmunity:
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multiple mechanisms acting simultaneously (ex graft rejection), different mechanisms at different stages, often undefined Ag
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Immunological Tolerance:
Possible Mechanisms: |
immune system learns to distinguish self/foreign
1) Central Tolerance: Clonal deletion/negative selection - T cells that recognize self Ags apoptose in the thymus 2) Peripheral Tolerance: Activation-induced apoptosis - activation of T cell induces expression of FasL Anergy Induction - direct induced tolerance of peripheral lymphocytes because costimulators aren't present, often occurs with autoreactive lymphos because self cells won't costimulate, can also occur with B cells if encounter Ag in absence of T cells, continue to circulate but unable to mount immune response Suppression - by Treg which may be made in thymus or periphery, probably suppress via cytokine secretion |
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Failure of Immuno tolerance -> Autoimmunity
Possible Mechanisms: |
Fail to activate induced cell death
Breakdown of T cell anergy Failure of suppression Molecular Mimicry - sequence similarities between foreign and self peptides cross-activate autoreactive T or B cells Polyclonal Lymphocyte activation Release of sequestered Ag's: ex - Ags of testis, eye, brain Epitope spreading/Exposure to cryptic Ag's: autoimmune response releases and damages self Ags, exposing previously unexposed epitopes (cryptic) which lymphocytes are not tolerant to, and new lymphos are continuously activated |
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Systemic Lupus Erythematosus:
general description affects who cause |
Type III hypersens, multisystem (many organs) autoimmune disease characterized by failure to maintain self-tolerance
genetic factors important but it is multigeneic more common in females, usually arises in 20s and 30s, may arise earlier or later wide array of autoAbs, especially ANA (anti-nuclear Abs): against DNA, histones, proteins bound to RNA, nucleolar Ags |
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SLE:
4 nuclear fluorescence patterns |
(pt may present with combination of these patterns)
1) Homogenous/Diffuse: Abs to chromatin, histones and sometimes dsDNA 2)Rim or Peripheral: Ab's to dsDNA 3) Speckled: (uniform or various sizes) Abs to non-DNA nuclear constituents (most common, least specific) 4) Nucleolar: a few spots within the nucleus, Abs to nucleolar RNA (most often with systemic sclerosis pt's) |
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SLE:
Possible Pathogenesis: Damage: |
Genetic susceptib -> environment trigger -> T and B stim -> Ab prod -> Ab-induced tissue damage
Malar (butterfly) rash on face, libman-sacks vegetation on heart valve Many tissues damaged Kidney most freq and severely damaged SLE death often from renal failure Also involved are skin, heart, BV's, brain, CT |
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Rheumatoid Arthritis:
general affects Rheumatoid factor Pathogenesis |
Chronic, systemic, Type III inflammatory disease
known as synovial joint disease, but affects many tissues (skin, BVs, heart, lungs, muscles) RF is IgM (mostly) produced by B cells in response to activated Th's, specific to Fc of IgG's -> forms complexes -> deposition Genetic suscept -> env trigger -> T stim -> B stim -> Ab/RF production -> T cell and Ab induced damage Includes: non-supperative inflamm of synovium with T, plasma, and macroph infiltrate -> synovium proliferates -> destroys articular cartilage -> pannus formation -> pannus bridges opposing bones -> fibrous ankylosis -> bony ankylosis Pannus = mass of synovium and synov stroma that grows over articular cartilage causing its erosion w/ inflamm cells, granulation tissue and fibroblasts |
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Amyloidosis:
Amyloid description |
Not an inflammatory disease, but believed to be byproduct of chronic inflamm
Amyloid = pathologic, pale pink, proteinaceous substance deposited between cells in many tissues, not all amyloid is chemically the same, amyloid is highly heterogeneous |
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Amyloidosis:
Amyloid types name - disease - source protein |
AL (amyloid light chain) - Myeloma/B cell tumors - Ig Light Chains from PLASMA cells
AA (amyloid associated) - Reactive/chronic Inflamm conditions - SAA (serum-amyloid associated, larger precursor of AA, synthesized in LIVER, circulates in assoc with HDL) AB2M - chronic renal failure - B2-microglobulin (component of MHCI, a normal serum protein) AB (B-amyloid protein) - Alzheimer's - amyloid precursor protein (encoded on chromosome 21) |
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Amyloidosis:
ID Damage |
Birefringence (double refraction - acting like a lens) when congo stained red -> dye binds to beta-pleated sheet conformation of anyloid -> then viewed under polarized light -> Amyloid grows bright green
Fills up tissue interstitium -> blocks, crowds out, causes atrophy of adjacent normal structures ALSO: AB amyloid of alzheimers may irritate and induce chronic activation of local microglia |
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Amyloidosis:
clinical features |
Shoulder pad sign - enlarged shoulders due to amyloid deposition
Lichen amyloidosis - scaly papules on skin, often on tibia Amyloid nodules |
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Diabetes Mellitus:
general description cause Diagnosis |
autoimmune destruction of B cells of Islet, probably T cell mediated, unknown B-cell specific Ag
strong genetic component Microsatellite mapping/gene scan: search for loci assoc with Type I diabetes 1) MHC locus - chrom 6 2) Insulin/IGF-2 - chrom 11 3) Possibly 18 other loci associated |
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Sjogren's Syndrome:
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Sjogren's - occurs mostly in women age 50-60
dry eyes and mouth due to autoimmune destruction of lacrimal and salivary glands via lymphocytic infiltration and fibrosis mostly Th and B cells with local Ab secretion often occurs in assoc with other autoimmune diseases 60% (esp RA) enlarged parotid gland, blurred vision, difficult swallowing, mouth fissures, recurrent bronchitis and pneumonitis, 40x increased risk of lymphoid malignancy (marginal zone lymphomas = neoplastic monoclonal B cell tumors) |
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Systemic Sclerosis and Scleroderma:
general affects what 2 types Pathogenesis |
chronic, unknown cause, abnormal accum of fibrous tissue in skin and multiple organs (throughout body)
affects skin (mostly), GI, kidney, heart, muscles, lungs 1) diffuse: onset is widespread skin involvement, rapid progression to early visceral involvement 2) Limited: Skin involvement only fingers, forearm, and face - may experience CREST (calcinosis - Ca deposits in soft tissue, raynaud, esophageal dismotility, sclerodactyly - thickening and tightness of skin on fingers and toes, telangiectasia - skin lesion from dilated BVs) Unknown cause but likely vascular damage and abnormal immune response -> local Growth factor accum -> act on fibroblasts, stim collagen production |
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Hashimoto's Thyroiditis:
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signif genetic component
enlarged thyroid and hypothyroidism immune syst reacts to variety of thyroid Ag's via ADCC, CD8 cytotoxicity, CD4 cytokine mediated death -> depletion of thyroid epithelial cells and severe follicular atrophy -> replaced by mononuclear cells and dense, keloid-like fibrosis -> hypothyroidism |
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Primary Immunodeficiencies:
Secondary Immunodeficiencies: |
almost always genetic, usuall show after 4-6 mo because of passive immunity, but may show earlier (typically pediatric diseases)
arises as complication from infection, malnutrition, aging, immunosuppression, irradiation, chemotherapy (for cancer and other autoimmune diseases) (typically adult diseases) |
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Primary Immunodeficiencies:
Types of mutations/abnormalities |
Global (affects all components)
Selective (only affects B or T cells) Restricted (affects subsets of T's or Ab types are abnormal/missing) Mutations in: cytokine or cytokine receptor adhesion molecule Complement component Complement regulators etc... |
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Seconday Immunodeficiencies:
Causes: |
Naturally occurring:
Tumors (lymphoma, myeloma, leukemia etc) malnutrition pregnancy Infectious: HIV-1 EBV Measles etc. Iatrogenic: chemotherapy radiation |
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Primary Immunodef:
1) X-linked agammaglobulinemia of Bruton: Defect Cause |
Failure of B cell precursors to mature into B cells (in the bone marrow)
The block in the pathway is no production of light chains to be added to the heavy chains which have already been rearranged Mutation in a cytoplasmic tyrosine kinase (B-cell tyr kinase = Btk) This gene is on the X chromosome (almost all Males) Btk is needed to transduce signals critical to B-cell maturation |
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Primary Immunodef:
1) X-linked agammaglobulinemia of Bruton: Clinical Manifestations: |
Low or absent serum B cells and IgG
Frequent and severe bacterial infections (chronic encephalitis, pharyngitis, sinusitis, otitis media, bronchitis, pneumonia) - almost always caused by H. influenza, S. pneumoniae or S. aureus (organisms usually opsonized by Abs) Giardia lamblia (intest. protozoan) infections common (usually opsonized by IgA) Increased risk of autoimmune disease (arthritis, dermatomyositis) High risk of poliomyelitis from vaccination |
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Primary Immunodef:
2) Common Variable Immunodef: Cause Types |
B cell developmental defects, affects both sexes, onset in later childhood or adolescence
Heterogeneous group of disorders (various causes) Common feature - generally affecting all Ab types, most pt's have normal or near normal B cells in blood but they can't different into plasma cells Possible Causes: B cell defect T cell defect in ability to activate B cells AutoAb to B or T cells |
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Primary Immunodef:
2) Common Variable Immunodef: Clinical Manifestations: |
Resemble those of X-linked agamma because of lack of Abs
Chronic upper resp, pulmonary, herpes virus, Giardia infections Susceptible to Verruca vulgaris (warts), aphthous ulcers (superfic invasion of oral flora), lymphoid interstitial pneumonitis (not infection, most likely chronic inflamm immune rxn) 20% autoimmune disease present (ex RA, vitiligo (melanocytes)) Increased risk of lymphoid malignancy and gastric cancer |
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Pimary Immunodef:
3) Hyper IgM syndrome: Cause |
T cell disorder - abnormal T cells can't induce B cells to make Ab types other than IgM, and can't activate macrophages to digest intracell microbes
No isotype switching from IgM to IgG, A, or E Abnormal B cell, Tc, and macrophage CD40/ Th cell CD40L(CD154) interaction |
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Pimary Immunodef:
3) Hyper IgM syndrome: Possible Mutations |
Mut CD40L (locus Xq26) - X-linked disease
Mut CD40 or activation-induced deaminase (DNA editing enzyme required for isotype switching) - autosomal recessive |
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Pimary Immunodef:
3) Hyper IgM syndrome: Clinical manifestations: |
Recurrent Pyogenic Infections (b/c opsonizing IgG's are low)
Recurrent Pneumonia (Pneumocystis carinii) (b/c cell med immunity defect) Serum has normal or increased IgM and no IgA or IgE, extremely low IgG Normal serum T and B cells |
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Primary Immunodef:
4) DiGorge Syndrome: cause: clinical manifestations: |
embryonic malform of 3rd and 4th pharyngeal pouches
-> failure to develop thymus and parathyroids -> unidentified gene on chrom 22 Tetany due to Ca++ dysregulation (PTH) Severe T cell deficiency, and T cell responses abnormal Normal B cells but lacking T cell help Congenital heart defects (primary cause of death) High suscept to Viruses and Fungi (ex Oral thrush = candida infection indicated T cell defic) Partial DiGorge exists and is self correcting |
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Primary Immunodef:
5) SCID: potential causes: Clinical manifestations: |
a group of disorders with defects in B and T cell response
Most common (50-60%) = X-linked mutation in common chain sharing many cytokine receptors Autosomal Mutations: - ADA (adenosine deaminase) deficiency -> predicted to lead to accum of deoxy-adenosine which is toxic to lymphos, especially T cells - JAK3 deficiency - Autosomal recessive Causes Immunological problems from birth (candida, GvHD, HSV, Varicella, pneumocystic carinii) |
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Primary Immunodef:
6) Genetic deficiencies of Complement System: Examples: |
Many are associated with SLE
C2 deficiency - most common, little to no increase in infection, but inc risk of SLE-like autoimmune disease (50% homozygotes develope SLE-like disease) C3 deficiency - recurrent pyogenic infect, glomeruloneph, increase autoimmune disorders C5, 6, 7, 8, 9 - recurrent neisserial (mening and gonococc) infections due to inability to mount MAC *C1 inhibitor deficiency = Hereditary Angioedema: autosomal dominant, common -C1 inhib blocks C1, factor XII (hagemann) of coag casc, Kallikrein, Plasmin |
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Primary Immunodef:
6) Genetic deficiencies of Complement System: C1 deficiency - Pathway: - Clinical Manifestations: |
Minor trauma -> Activated F XII -> Plasminogen to Plasmin -> Activated C1 -> Complement cascade -> anaphylaxotoxins -> edema
episodes of edema of the skin, mucosal surfaces (ex lips, face, hands, larynx and GI) Can cause life-threatening asphyxia, nausea, vomiting, diarrhea |
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Secondary Immunodef:
Types: |
Lymphoma (B cell, T cell, or Hodgkins
Chemotherapy HIV-1 |
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Secondary Immunodef:
1) HIV: Description: Genome: |
Retrovirus - contains reverse transcriptase, integrase and protease with dsRNA
Genome - -LTR (long terminal repeat) binds host transc factors, required for transcrip initiation, virus will be activated when immune syst is activated -env (gp160 envelope protein)cleaved in ER -> gp 120 (mediated CD4 and chemokine receptor binding) and gp41 (mediates fusion with Th) -tat (Transcriptional activator p14) enhances viral DNA replication by RNA polII -rev (regulator of viral gene expression p19) promotes nuclear export of incomplete spliced viral RNAs -nef (Negative Effector p24) down-regulates CD4 and MHCI to make invisible to Tc cells, block apoptosis, enhance infectivity |
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Secondary Immunodef:
HIV: Pathogenesis: |
-CD4 on Th cells = high affinity HIV receptor, gp120 must also bind to chemokine receptors for entry
(mutations in chemokine coreceptors can inhibit or delay HIV infection) -Gp41 tip inserts a fusion peptide into host cell and transfers HIV genome -Reverse Transcription -> cDNA (Proviral DNA) -cDNA can a) remain in cytoplasm in linear form if cell is quiescent b) Circularize in dividing cells, enter nucleus and integrate into host (may remain latent for months or years) c) Cytokine activation of cell causes proviral DNA transcription - complete particle formation and budding -> cell death |
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Secondary Immunodef:
1) HIV 3 ways for Th cells to die: |
a) Viral replication and budding
b) activation-induced apoptosis of uninfected cells c) Expression of HIV peptides on infected cells -> Hive-specific Tc cell-mediated cytotoxicity |
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Secondary Immmunodef:
1)HIV: Histology: Secondary Conditions: |
Early HIV Infection: Lymph node hyperplasia, lots of T cells in T cell zones
AIDS: Lymph node filled with macrophages instead of T and B cells, T cell mediated macrophage activation is gone 1)Mycobacterium avium intracellulare (macrophages become full of mycobacteria they can't kill) 2)Herpes zoster (shingles) 3)Cytomegaloinfection of heart 4)Pneumocystis carinii 5)Toxoplasmosis 6)Kaposi's Sarcoma - tumors, HHV8 (human herpes virus 8) creates lesions inside and outside body (GI hemorrhage), infects spindle cells -> proliferate and induce vascularization 7)Primary CNS Lymphoma: (CNS is the second target organ beyond the immune syst) lesions created by B cell lymphomas throughout the brain |
