1) Autoimmunity

What is autoimmunity? Why do autoimmune reactions persist?

→ inappropriate adaptive immune response characterized by the loss of self-tolerance and the large production of autoantibodies and autoreactive T cells

• usually persist once initiated b/c the inciting self-antigen can’t be cleared without the complete destruction of the target tissue

What are the 2 important contributors in an autoimmune reaction?

1. Autoantibodies

2. Autoreactive T cells

What is the threat from destruction of an organ/tissue in an autoimmune reaction?

inciting self-antigen remains present and continues to drive the immune response → can’t be cleared unless the target tissue is completely destroyed

Classify the 2 types of autoimmune disease with some examples?

1. Organ-specific

   • reaction is localized to a particular organ

   • e.g., Hashimoto’s thyroiditis, 1er myxedema, thyrotoxicosis, pernicious anemia, Addison's disease, insulin-dependent DM, MG

2. Non-organ specific (systemic)

   • reaction involves many tissues throughout the body

   • e.g., systemic lupus erythematosus (SLE), RA, scleroderma, dermatomyositis

What are the changes in thyroid gland as a result of Hashimoto’s thyroiditis?

→ normal architecture of the gland is destroyed and replaced by invading cells (e.g., lymphocytes, macrophages, and plasma cells)

• characterized by infiltration of inflammatory lymphoid cells and 2er lymphoid follicles formation with germinal centers

• gland appears pale and firm rather than the normal red and soft texture

What are its sx of Hashimoto’s Thyroiditis?

• goiter formation (enlarged thyroid)

• hypothyroidism (low TH produced)

• upper eyelid retraction

What are the 2 targets for autoantibodies in Hashimoto’s thyroiditis?

1. Thyroglobulin

2. Thyroid peroxidase

What are the 2 main consequences of Hashimoto’s thyroiditis?

1. Hypothyroidism

2. Goiter formation

What is Grave’s disease and its characteristic features?

→ common cause of hyperthyroidism resulting from the over-production of TH

• thyroid enlargement (diffuse goiter), exophthalmos (bulging eyes), heat intolerance & anxiety

Identify thyroid diseases that involve thyroid destruction vs stimulation of TH synthesis.

Thyroid destruction

• Hashimoto's thyroiditis

• Hashimoto's persistent goiter

• "hashitoxicosis"

• 1er myxedema

.

Stimulation of TH synthesis

• Graves' disease

• Non-goitrous hyperthyroidism

• "hashitoxicosis"

What type of disorders is SLE? What is the target of SLE antibodies in a tissue?

→ systemic autoimmune disease

• antibodies target the cell nucleus

What are the common ocular manifestations of SLE?

• Keratoconjunctivitis Sicca (dry eye)

• Retinal vasculitis

• Blepharitis

• Chalazion

Give some examples of diseases where autoimmune conditions can coexist.

• Pernicious anemia (gastric autoimmunity) can have ↑ thyroid antibodies

• 1er Sjogren’s syndrome can have concomitant autoimmune hypothyroidism

• SLE and Sjogren’s syndrome have a 2^nd, 3^rd, or 4^th autoimmune disease

What are the ocular manifestations of Myasthenia Gravis?

1. Ptosis

2. Diplopia

What are the ocular manifestations of RA?

1. Dry eye

2. Scleritis

3. Uveitis

Identify the autoantibodies existing in bronchial asthma and Guillain-Barre syndrome.

Bronchial asthma: Autoantibodies to α-adrenergic receptors

Guillain-Barré syndrome: Na⁺ channel autoantibodies

What are the 2 major types of dry eye?

1. Aq-deficient (Sjogren's & non-Sjogren's)

2. Evaporative (lipid-deficient, lid-related & surface change)

How do cytokines influence inflammation in dry eye?

→ affect both the ocular surface & lacrimal gland

• ↓ tear production & clearance lead to:

  • inflammatory cell infiltration

  • ocular surface inflammation

  • activates surface epithelium to release more adhesion molecules & cytokines

Identify the common cytokines found in patients with dry eye vs allergic conjunctivitis.

Dry eye: TNF-α, IFN-γ, IL-1, IL-6, IL-8

Allergic conjunctivitis: IL-4

What are the 2 common subsets of T cells and their cytokine secretions?

1. T helper 1 (TH1) cells makes IFN-γ & TNF-α

2. T helper 2 (TH2) cells makes IL-4, IL-5, IL-13

Briefly explain the sequence of events involved in dry eye mediated inflammation involving APCs and T cells.

1. APCs (e.g., macrophages) infiltrate inflamed tissue and engulf foreign antigens

2. Process the antigens into peptides and present them via MHC II molecules

3. T cells with specific receptors recognize these antigens and become activated via costimulatory molecules

4. In the desiccating atmosphere of a dry eye, a TH1-inducing environment is created → CD₄⁺ T cells differentiate into TH1 cells

What are the 2 pathways activated in Type I hypersensitivity response and the end products of the pathways?

1. Granule Release - releases preformed mediators (e.g., histamine, tryptase, cytokines)

2. Phospholipase A2 Activation - makes newly synthesized mediators (e.g., prostaglandins, thromboxane A & leukotrienes)

Name some common mediators released due to activation of mast cells.

• Histamine

• Cytokines

• tryptase

• Prostaglandins

• Leukotrienes

• Heparin

• Chymase

What are the 2 phases involved in Type 1 hypersensitivity response and their main effects?

1. Sensitization phase - Initial exposure to an antigen → IgE binding to mast cells/basophils

2. Activation phase -Reexposure to the antigen triggers degranulation → ↑ vessel permeability, bronchial constriction, mucus secretion, urticaria

What are the 2 main mechanisms of immunopathological damage in Type 2 hypersensitivity reaction?

1. Classical complement pathway - causes lysis via the MAC

2. Antibody-dependent cell cytotoxicity (ADCC) - NK cells release perforin & granzyme

What is the mechanism involved in Type 3 hypersensitivity reaction?

involves the deposition of antigen-antibody (Ag-Ab) complexes in tissues → induces complement activation and massive neutrophil infiltration

Identify 2 diseases involving that uses a Type 3 hypersensitivity reaction.

1. SLE

2. RA

What is the mechanism involved in Type 4 hypersensitivity reaction?

cell-mediated reaction where sensitized TH1 cells release cytokines that activate macrophages or cytotoxic T cells (CTLs) → direct cellular damage and tissue injury

Identify a disease involving Type 4 hypersensitivity reaction.

Type 1 insulin-dependent diabetes

What are the 2 important influential factors involved in autoimmune disease?

1. Genetic factors

2. Environmental influences

Explain with an example how genetic factors can play a role in manifestation of additional autoimmune disorders.

→ Genetic factors predispose individuals to autoimmunity→ clustering of distinct autoimmune diseases within families

• e.g., families with RA may show other autoimmune disorders, and relatives of patients with Hashimoto’s thyroiditis or pernicious anemia have a higher incidence of thyroid autoantibodies

Specify the chromosome number and location of MHC region that contributes to disease susceptibility in several autoimmune disorders?

MHC region is located on the short arm of chromosome 6

What disease-associated alleles are associated with type 1 DM?

DR3/4

What disease-associated alleles are associated with RA?

DR4

What disease-associated alleles are associated with SLE?

• HLA-A1

• B8

• DR3

What is the HLA gene associated with ankylosing spondylitis?

HLA-B27

Name some autoimmune diseases associated with PTPN22.

• T1D

• RA

Briefly explain the stages during progression of autoimmune disease.

1. Genetic and other factors create a predisposition to autoimmunity

2. Environmental trigger (e.g., infection or UV radiation) initiates the loss of self-tolerance + autoantibody production

3. Autoimmune attack causes tissue damage → release of more self-antigens, propagation of the response, and clinical sx

Briefly explain the autoimmune mechanism involving APCs and B cells.

1. An immune complex of autoantigen and a natural autoantibody is taken up by an APC

2. APC presents processed segments of the antibody to T_H cells

3. B cells that express “pathogenic autoantibodies” capture these complexes and receive help from the T_H cells to begin autoantibody synthesis

Identify the sequential events involved in induction of autoimmunity by microbial antigens.

1. Naive T_H cells initially fail to recognize ↓ [autoantigen] on tissue cells

2. ↑ [Cross-reacting microbial antigen] is presented by a "professional" APC with co-stimulators like B7

3. This primes the T_H cells, ↑affinity and expression of accessory molecules like LFA-1 & CD2

4. Primed T-cells no longer require co-stimulatory signals and can now react with self-epitopes on "nonprofessional" APCs (like epithelial cells) → disease

How do cross-reactive foreign antigens induce autoantibody production?

1. B-cellsrecognize an epitope shared by an autoantigen and a foreign antigen

2. While they normally receive no help b/c autoreactive T_H cells are deleted, they can present peptides from a cross-reacting foreign antigen to non-autoreactive T cells

3. T-cells drive the B-cells to proliferate and secrete autoantibodies

How is direct stimulation of autoreactive cells by foreign antigen achieved? Give an example.

→ autoreactive effector cells can be directly triggered by an antigen or stimulator, bypassing the need for T-cell help

• e.g., LPS or Epstein–Barr virus → directly stimulate B-cells

What is the influence of infection in an autoimmune disease? Give an example.

→ Infection may trigger a relapse in autoimmune diseases

• e.g., chronic S. aureus nasal carriage is associated with more frequent relapses of upper resp tract disease

What is the gene influencing cytokines that is implicated in autoimmune disease?

IL2RA

How can introduction of a transgene induce an autoimmune reaction? Give an example.

→ transgene cause MHC upregulation in specific cells

• e.g., introducing a transgene for IFN γ into pancreatic β-islet cells upregulates MHC class 2 genes → autoimmune destruction of those cells

What class of MHC molecules is implicated in Grave’s disease?

MHC class 2

What changes occur during myasthenia gravis? Give examples.

→ Autoantibodies block Ach receptors on the post-synaptic membrane, acting as antagonists → muscle weakness & fatigability

• e.g., occurswhen these antibodies cross the placenta, causing transient muscle weakness in newborns

What do autoantibodies target in bronchial asthma and Guillain-Barre syndrome?

Bronchial asthma: α-adrenergic receptors

Guillain–Barre syndrome: Na⁺ channels

Describe the mechanism involved in development of Pernicious anemia.

1. Plasma cells in the gastric mucosa secrete autoantibodies against intrinsic factor into the stomach lumen

2. This antibody interferes with the binding of Vitamin B12 to intrinsic factor → prevents the complex from being transported across the intestinal mucosa for absorption

How do autoantibodies bring about the damage in RA?

1. Autoantibodies provoke damage by stimulating macrophages & fibroblasts via cytokines and immune complexes

2. Complexes formed by IgG rheumatoid factors specific for Fcγ domains, are often deficient in terminal galactose on Fc oligosaccharides

3. This "agalacto" glycoform causes inflammation by reacting with mannose-binding lectin & inducing TNF α production

How is pernicious anemia and Mg controlled metabolically?

Pernicious anemia: Vitamin B12 injection

MG: Administrating cholinesterase inhibitors

What are the 2 approaches of targeting B cells in SLE?

1. Anti-CD20 (e.g., Rituximab)

2. Anti-CD22/anti-Blys (transmembrane activator-IgG)

What are the 4 biological agents used to target TNF α?

1. Infliximab

2. Adalimumab

3. Etanercept

4. Certolizumab

What are the targets of Rituximab, toclizumab, abatacept and anakinra? Give their application.