Lecture 21 - Immune tolerance and autoimmunity

Explain the role of genetic susceptibility in autoimmunity

-Common in autoimmune diseases

-Triggered by mutations in immune regulation genes

What do GWAS (Genome-wide association studies) show?

-Correlation between disease frequency and genetic variant

-Involve autoimmune disease patients and healthy individuals

What are monogenic autoimmune diseases? What genes do they normally affect?

-Single gene mutation causing a high risk of autoimmunity

-Affect genes critical for preventing autoimmune responses

How is genetics related to T_H1 and T_H17 hyperactivation?

Genes linked to T-cell responses, DC or T-cell function, and in different steps of immune pathway

What is important to remember about genetic involvement in autoimmunity?

One gene may contribute to multiple autoimmune diseases

How do MCH gene variants cause disease?

-Vary in their ability to bind to self-Ag peptides

-Inefficient presentation of self-Ag peptide during negative selection

What may occur with genes that impair innate immune responses?

Predispose to chronic T-cell mediated inflammatory disease

What is an example of a disease caused by genetic impairment of innate immune system? What is changed?

-Crohn’s disease

-Causes hyperactive CD4 T-cells that react to commensal gut microbiota

What are the two genes associated with Crohn’s disease? What do each do?

1. NOD2 - recognizes microbial Ag (kill/inhibit bacteria cells)

2. ATG16L1 and IRGM - involved in clearance of phagocytosed bacteria

What does a mutation in NOD2 cause? What about ATG16L1/IRGM?

-NOD2 = reduce antimicrobial peptide release

-ATG16L1/IGRM - impaired bacterial clearance (cause chronic inflammation)

What is bystander cell activation?

Inflammatory mediators activate nearby lymphocytes not specific for the pathogen (may be autoreactive)

How does an infection cause tissue destruction?

Release of sequestered self antigens cause breakdown of immunological ignorance

What is molecular mimicry?

Pathogen antigens resemble self antigens, triggering cross-reactive immune responses

What type of hypersensitivity is primary IMHA? What is the definition? What is the pathogenesis? What are the clinical signs? What is the diagnosis and treatment?

1. Hypersensitivity - Type II

2. Definition - autoimmune destruction of RBCs

3. Pathogenesis - autoantibodies bind to RBCs, complement activation, extravascular hemolysis (liver/spleen), intravascular hemolysis (MAC)

4. Clinical signs - pallor, weakness, tachycardia, tachypnea, icterus, bilirubinuria, splenomegaly

5. Diagnosis - coomb’s test and CBC

6. Treatment - immunosuppression, supportive care and transfusion

What type of hypersensitivity is Evans syndrome? What is the definition? What is the pathogenesis? What are the clinical signs? What is the diagnosis and treatment?

1. Hypersensitivity - type II

2. Definition - combination of IMHA and immune mediated thrombocytopenia (IMTP)

3. Pathogenesis - autoantibodies target RBCs, platelets, and sometimes neutrophils

4. Clinical signs - pallor, weakness, icterus, petechia, ecchymoses, mucosal bleeding

5. Diagnosis - evidence of hemolytic anemia, thrombocytopenia

6. Treatment - immunosuppression and supportive care

What type of hypersensitivity is myasthenia gravis? What is the definition? What is the pathogenesis? What are the clinical signs? What is the diagnosis and treatment?

1. Hypersensitivity - type II

2. Definition - neuromuscular disorder caused by impaired transmission at NMJ

3. Pathogenesis - autoantibodies formed against ACh receptors

4. Clinical signs - exercise induced weakness, collapse, megaesophagus

5. Diagnosis - AChR Ab test

6. Treatment - Acetylcholinesterase inhibitor, immunosuppressive therapy, supportive care

What type of hypersensitivity is systemic lupus erythematosus (SLE)? What is the definition? What is the pathogenesis? What are the clinical signs? What is the diagnosis and treatment?

1. Hypersensitivity - type III

2. Definition - Auto-Ab production against nuclear antigens

3. Pathogenesis - autoantibodies and self-antigens form immune complexes that deposit in tissues

4. Clinical signs - polyarthritis, glomerulonephritis, skin lesions, fever, lethargy, lymphadenopathy

5. Diagnosis - Positive antinuclear Ab (ABA) test, clinical signs involving 2 or more organ systems, exclusion of infectious/neoplastic causes

6. Treatment - immunosuppressive therapy, supportive care

What type of hypersensitivity is sutoimmune thyroiditis? What is the definition? What is the pathogenesis? What are the clinical signs? What is the diagnosis and treatment?

1. Hypersensitivity - type IV

2. Definition - autoimmune destruction of thyroid follicle

3. Pathogenesis - autoreactive T-cells drive tissue destruction, thyroid damage reduces thyroid hormone production

4. Clinical signs - lethargy, weight gain, cold intolerance, bradycardia, mental dullness, alopecia, dry coat, hyperpigmentation, recurrent skin infections

5. Diagnosis - Serum T4 (low) and T3 (high), antithyroglobulin Ab titers

6. Treatment - lifelong thyroid hormone replacement, supportive care