Unit 3 Immunology

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U3 W 3
Diarrhea

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Nonspecific immune defense mechanisms of the intestinal mucosa

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Epithelial cell barrier
Mucus
Gastric acid
Proteolytic enzymes
Normal flora: Changes can cause pathogenic bacteria to flourish (i.e. Clostridium difficile)
Motility

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Immune defense mechanisms of the gut-associated lymphoid tissue (GALT)

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IgA Secreted by plasma cells in saliva, respiratory system, gut, etc.

Peyer's patches

M cells

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Peyer's patches

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Lymphoid follicles* covered by specialized epithelium

B cells primed here leave Peyer’s patches via lymphatics, then “home” back to lamina propria (+ other mucosal sites), maturing there into IgA-secreting plasma cells

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M cells

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Specialized epithelial cells that cover Peyer’s patches

Have many small folds on basolateral surface giving them their name (M stands for Microfold)

M cells actively transport antigens from lumen across epithelium into dendritic cell rich area;
delivers these antigens into underlying lymphoid tissue where T and B cells are primed

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3 molecules essential for lymphocyte homing to the lamina propria

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(1) CCR9 (chemokine receptor) : expressed by T cells in lamina propria

(2) MAdCAM-1 (Mucosal Addressin Cellular Adhesion Molecule-1): expressed by blood vessels in lamina propria, is a ligand for (3) a4b7 integrin

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Intraepithelial Lymphocytes (IELs)

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Mostly CD8+ T cells

CD45RO+

Sustain epithelial integrity by rapidly eliminating infected and damaged cells

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Lamina Propria Lymphocytes (LPLs)

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CD4+ and CD8+ T cells (T cells predominate over B cells by 4:1, NK and plasma cells are also present)

CD45RO+

Many roles

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7 Steps of how Naïve B cell differentiation into a plasma cell producing IgA

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1: Stem cell differentiates into B cell which productively rearranges HC/LC genes while in the bone marrow
2: Naïve B cell expressing IgM & IgD migrates through blood into follicles of lymphoid tissues (including Peyer’s patches)
3: Antigens transported by M cells of Peyer’s patch are picked up by Dendritic Cells and processed
4: Peptides from antigens are presented on MHC Class II molecules to naïve CD4+T cells
5: Naïve T cells become activated CD4+ TH cells that express CD40L and secrete cytokines
6: Naïve B cells (express CD 40) bind antigen, process & present peptides f/ antigen to CD4+ TH cells
7: B cells isotype switch to IgA, influenced by cytokines (predominantly TGF-B) produced mainly by nonlymphoid cells at mucosal sites [Signals from B cell activation factor (BAFF) and a proliferation ligand (called APRIL) assist in process]

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Structure and function of immunoglobulin isotypes (IgA vs others)

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IgA (dimers); IgM (pentamers)

IgA:
Serum has some (mostly monomeric)
Main production/function at mucosal sites
Neutralizes microbes/toxins
NOT opsonizing antibody (FcaRs exist; function unknown)
Does NOT bind/mediate lysis by complement

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Transport of dimeric IgA across mucosal epithelial cells (7 steps)

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1. Plasma cells synthesize J chain (J = joining)
2. J chain associates/helps form polymers: IgA (dimers), IgM (pentamers)
3. Mucosal epithelial cells express polymeric immunoglobulin receptor (pIgR)
4. pIgR (with IgA*) is endocytosed, crosses epithelial cell to apical (luminal) surface (*pIgR will transport IgM if it is available. In IgA deficient individuals, IgM is probably the main Ig transported.)
5. pIgR is cleaved, releasing IgA w/ a part of pIgR still attached
6. This part of receptor, called secretory component (SC), remains attached to IgA and helps protect it from proteolysis
7. IgA w/ secretory component attached is called secretory IgA (sIgA)

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Polymeric immunoglobulin receptor (pIgR),

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transmembrane receptor that translocates polymeric Igs across epithelial barrier.

After synthesis, pIgR is delivered to basolateral surface of epithelial cell where dimeric IgA associates (or pentameric IgM to a lesser extent)

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Rational for oral administration of rotavirus and polio vaccines

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Oral vaccination induces secretory IgA (sIgA), which binds viral surface antigens, prevents viral attachment to mucosal cells. sIgA/virus complexes removed from body by peristalsis

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Inactivated Polio Vaccine (IPV, Salk)

advantages/disadvantages

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Advantage: No risk of vaccine-associated polio paralysis

Disadvantage: Only low levels of viral neutralizing IgA in gut; vaccinees infected w/ wild-type virus are carriers (virus can multiply in intestines, be shed in stools)

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Oral Polio Vaccine (OPV, Sabin)

advantages/disadvantages

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Advantage: Vaccinee cannot act as carrier (IgA/virus complexes shed in stools are not infective!)

Disadvantages:
Vaccinees may spread vaccine virus in community.
Danger of reversion to virulence.
3 attenuated strains interfere with each other's replication (3 doses are required)

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Oral Rotavirus Vaccine

Advantages/ Disadvantages

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AD: Oral vaccine induces production of sIgA which neutralizes virus at point of entry/prevents infection

DISAD:
First live, attenuated, oral vaccine associated w/ as high as one case of intussusception for every 5000 to 9500 vaccinated infants (highest risk after first dose)
No evidence of new live, oral vaccines being unsafe

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Primary immune Deficiencies

name them (8)

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1. X-linked agammaglobulinemia (Bruton’s disease)*
2. Common variable immunodeficiency disorder (CVID)
3. Hyper-IgM syndrome:
CD40L deficiency*
4. IgA with IgG subclass deficiency
5. IgA deficiency
6. SCID (4 types)
7. Bare Lymphocyte Syndrome
(BLS)
8. IL-12 pathway deficiency

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X-linked agammaglobulinemia (Bruton’s disease)*

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Most common defect: B cell Tyrosine Kinase (BTK)
Immunodiagnosis: B cells are absent;
all serum Igs are low
Reason for Diarrhea: Infection:
Giardia; Enterovirus

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Comon variable immunodeficiency disorder (CVID)

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Most common Defect: Unknown block in B cell maturation
Immunodiagnosis: B cells are present, but often decreased;
all serum Igs are low
Reason for Diarrhea: Infection:
Giardia:Enterovirus

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Hyper-IgM syndrome:
CD40L deficiency*

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Most common Defect: CD40L1
Immunodiagnosis: B cells are present; low serum IgA, IgG; high serum IgM
Reason for Diarrhea: Infection: Giardia; Cryptosporidium; Salmonella; Entamoeba histolytica

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IgA with IgG subclass deficiency

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Most Common Defect: Unknown
Immunodiagnosis: B cells are present;
IgA together with certain IgG subclasses are absent or nearly absent
Reason for diarrhea: Giardia Infection

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IgA deficiency

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Most Common Defect: Unknown
Immunodiagnosis: B cells are present;
IgA is absent or nearly absent
Reason for diarrhea: Higher risk for developing autoimmune disease (possibly affecting GI tract)

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Commonest form of SCID!

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Most Common Defect: IL-2/4/7/9/15R y chain (the receptors for these cytokines all share this chain)
Immunodiagnosis: T cells (-, absent), B cells (+, present), NK cells (-, absent)
Reason for diarrhea: Often viral

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SCID

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Most Common Defect: ZAP-70
Immunodiagnosis: T cells (-, absent), B cells (+, present), NK cells (-, absent)
Reason for diarrhea: Often viral

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SCID

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Most Common Defect: CD3
Immunodiagnosis: T cells (-, absent), B cells (+, present), NK cells (-, absent)
Reason for diarrhea: Often viral

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SCID

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Most Common Defect: RAG gene
Immunodiagnosis: T cells (-), B cells (-), NK cells (+)
Common infections causing diarrhea: often viral

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Bare Lymphocyte Syndrome

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Most Common Defect: MHCII gene transcription
Immunodiagnosis: T cells (+), B cells (+), NK cells (+)
Common infections causing diarrhea: often viral

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IL-12 pathway deficiency

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Most common defect: IL-12, IL-12R
Common infection causing diarrhea: Salmonella

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U3 W5
Abominal pain & GI bleed

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Into to immunology of cancer

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Tumor specific antigen

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Agn found only on tumor cells

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Tumor-Associated Agn

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Agn found on tumor cells, but also on some normal cells

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Oncofetal Agn

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Agn expressed at high levels in cancer cells or normal tissues during development, but not in adult tissues

Eg: Carcinoembryonic Agn (CEA) and alpha-fetoprotein (AFP)

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Differentiation Agn

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Agn specific for cellular lineage/differentiation stage f/ which tumor originated

Eg: CD20 or Ig idiotypes in B-cell lymphoma; and Prostate-specific Agn (PSA)

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Example of a mutated gene product as a tumor Agn

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Mutated tumor suppressor genes like p53

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exmaples of overexpressed or aberrantly expressed cellular (self) proteins as tumor agns

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overexpresse - TYROSINE in Melanoma

aberrantly expressed - MAGE AGNS on a variety of tumor types

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Examples of proteins produced by oncogenic viruses as a type of tumor antigen

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HPV & EBV viral proteins

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Examples of Altered cell sufrace glycolipids or glycoproteins (over expressed or abnormal forms) as a type of tumor antigen

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Overexpressed - certain GANGLIOSIDES (GM2, GD2) in melanoma

Abnormal forms - HYPERGLYCOSYLATED MUCIN (MUC-1) in many breast, colon, and pancreatic cancers

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Carcinoembryonic antigen
(oncofetal agn)

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 Intercellular adhesion molecule expressed in gut, pancreas and liver during first two trimesters of gestation
 Expression INCREASED IN CANCERS OF COLON, PANCREAS, STOMACH, & BREAST (demonstrated using immunohistochemical techniques)
 Serum CEA level used to monitor tumor presence/recurrence (however, serum CEA can ALSO BE ELEVATED IN CHRONIC INFLAMMATORY CONDITIONS OF BOWEL AND LIVER)

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Alpha-Fetoprotein
(oncofetal antigen)

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 Circulating glycoprotein (replaced by albumin in adult) synthesized/secreted by fetal yolk sac/liver
 AFP is used in immunohistochemistry to aid pathologic identification of tumor cells on tissue sections
 Serum AFP levels can be elevated in patients with LIVER and TESTICULAR germ cell (occasionally gastric and pancreatic) cancer
 Elevated serum AFP is useful indicator of advanced LIVER cancer or recurrence after treatment (however, serum AFP can also be elevated in CIRRHOSIS of liver)

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Prostate-specific antigen
(differentiation antigen)

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 Serum protease normally secreted by prostatic epithelium
 Serum PSA level is important test used in diagnosis and management of prostate cancer (however, serum PSA can also be elevated in PROSTITIS and BENIGN PROSTATIC HYPERPLASIA)

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Anti-tumor Effector Mechanisms:

Direct killing (apoptosis) of tumor cells by cytotoxic T lymphocytes

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Cell type: Tumor antigen-specific CD8+ T cells

Major adaptive immune defense mechanism against tumors!

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Anti-tumor Effector Mechanisms:

Direct killing (apoptosis) of tumor cells by natural killer (NK) cells

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Cell type: NK cells

First line of innate defense against tumors;
important defense against tumors that fail to express MHC I

cytokines: IL-2 (& IL-15*) promote differentiation & activation of NK cells

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Anti-tumor Effector Mechanisms:

Reactive oxygen species or TNF from activated macrophages

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cell type: Macrophages

cytokines: IFN-g from CD4+ TH1 or NK cells activates macrophages

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Anti-tumor Effector Mechanisms

Antibodies

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cell type: Plasma cells (B cells)

Monoclonal antibodies (like anti-CD20 for lymphomas) are used therapeutically;
h/e naturally occurring anti-tumor antibodies are generally ineffective in vivo

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Mechanisms By Which Tumors Evade Immune System

Selective outgrowth of “antigen-loss” tumor cell variants

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Host: Failure of antigen-specific anti-tumor responses

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Mechanisms By Which Tumors Evade Immune System

Reduced MHC I expression

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Host: Antigen-specific CD8+ CTL response fails
(If MHC I expression is lost completely,
NK cells may eliminate tumor cells)

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Mechanisms By Which Tumors Evade Immune System

No expression of costimulatory molecules (B7-1/B7-2 aka CD80/CD86)

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Host: T cells may become anergic (unresponsive/tolerance) or even undergo activation induced cell death (deletion)

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Mechanisms By Which Tumors Evade Immune System

Suppression of host immune response (i.e. tumor produces TGF-b; tumor stimulates production of regulatory T cells)

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Host: Immune responses are suppressed

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Mechanisms By Which Tumors Evade Immune System

Expression of glycocalyx molecules that mask tumor antigens

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Host: Antigen-specific anti-tumor responses fail

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Mechanisms By Which Tumors Evade Immune System

Expression of FasL

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Host: Fas-expressing (activated) antigen-specific anti-tumor T cells are killed

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General Types Of Tumor Immunotherapy:

Monoclonal antibodies; also, monoclonal antibodies coupled to potent toxins

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Anti-CD20 is used to treat B cell tumors (stem cells do not express CD20, so normal B cells are replenished after treatment is stopped)

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General Types Of Tumor Immunotherapy

Vaccination with
Tumor-antigen “pulsed“ dendritic cells, or
DNA encoding tumor antigens (sometimes accompanied by DNA encoding cytokines), or
Dendritic cells transfected with this DNA
(“pulsed” means that the dendritic cell would have time to pick up & present antigen)

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Activates tumor-specific CD8+ CTLs
(immunogenic tumor antigens are being sought)
(transfected dendritic cells produce the tumor antigen and present it both on MHC1 to CD8+ CTLs and on MHCII to CD4+TH1 cells)

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General Types Of Tumor Immunotherapy

Vaccination with tumor cells transfected with DNA encoding costimulatory molecules (B7) or cytokines (IL-2; others) or both; systemic cytokine therapy

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Augments host’s immunity to tumor; systemic administration of cytokines can have very toxic side effects

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General Types Of Tumor Immunotherapy

Adoptive cellular therapy using Lymphokine Activated Killer cells or Tumor infiltrating lymphocytes

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LAKs = Lymphokine Activated Killer cells (mostly NK cells) are generated by EXPANDING PT PERIPHERAL WBCs in culture USING IL-2, then reinfusing into patient. This is an older technique and efficacy has been variable. A newer approach is to use TILs

TILs = Tumor infiltrating lymphocytes (CTLs and NK cells) are generated by EXPANDING LYMPHOCYTES isolated from tumors in culture using IL-2. Human trials with TILs are ongoing

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Serum marker for...
Colon cancer

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CEA

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Serum marker for...
Liver cancer

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AFP

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Serum marker for...
Prostate cancer

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PSA

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Example of tumor antigen type...
Oncofetal antigen

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CEA

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Example of tumor antigen type...
Differentiation antigen

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PSA

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Example of tumor antigen type...
Product of mutated gene

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p53

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Example of tumor antigen type...
Oncogenic viral protein

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HPV viral protein