Untitled Quiz

Autoimmunity

• Autoimmunity describes immune reactivity targeting the body's own tissues (self).
• This can involve antibody-mediated or cell-mediated immune responses.
• Autoimmunity results from a breakdown in tolerance to self-antigens.
• Autoimmune diseases can be systemic (affecting many organs) or organ-specific.
• The diseases tend to be chronic, progressive, and self-perpetuating.

Objectives

• Define autoimmunity.
• Describe the immunological basis of autoimmunity.
• List and discuss main autoimmune diseases in veterinary species.

What is Autoimmunity?

• Autoimmunity is immune reactivity against the body's own constituents (self).

General Features of Autoimmune Disorders

• Autoimmunity results from the lack of induction or maintenance of tolerance to self-antigens.
• Autoimmune diseases can be systemic or organ-specific.
• Various effector mechanisms cause tissue injury in different autoimmune diseases.
• Autoimmune diseases tend to be chronic, progressive, and self-perpetuating.

Principles of Autoimmune Disease

• Genetic conditions, particularly MHC genes, strongly associate with autoimmunity.
• Self-antigens may be abnormally displayed or have structural changes.
• Infections or cell injury can elicit initial innate immune responses.
• Normal immune responses may be triggered by cross-reactivity with antigens of infectious agents.

Certain Autoimmune Responses are Physiological

• Examples like red blood cell (RBC) elimination at the end of their lifecycle.
• Phagocytosis (cell eating) plays a key role in removing aged RBCs
• CD47 shedding from aged RBCs facilitates phagocytosis by macrophages.

Immune Response to Hidden Antigens

• Many self-antigens remain hidden, preventing immune tolerance development.
• Lymphocytes generally develop tolerance in the thymus to self-antigens.
• Damage to tissues can expose hidden self-antigens leading to autoimmunity.

Certain Auto-antigens are Located in Sites without T Cell Circulation

• New antigens appear in testes after sexual maturation.
• Autoimmune reactions may occur upon damage to testes, leading to the release of antigens (e.g., sperm) into the circulation.
• Myocardial infarction (heart muscle damage) can lead to auto-antibodies targeting heart muscle mitochondria).

Antigens Generated via Molecular Configuration

• New epitopes (antigen-binding sites) can arise on normal proteins.
• Rheumatoid factor (RF) is an example of autoantibodies targeting other immunoglobulins.
• Changes in immunoglobulin configuration, specifically the Fc region, can expose new epitopes.
• Systemic lupus erythematosus (SLE) is a disease where large amounts of antigen-antibody complexes are generated, leading to RF production.

Molecular Mimicry

• Infectious agents' antigens can mimic self-antigens.
• This triggers an immune response that targets both the pathogen and self-antigens
• Trypanosoma cruzi infection, for example, can induce antibodies that react with neural and heart muscle tissues.
• Epstein-Barr virus (EBV) DNA polymerase can cross-react with myelin basic protein, potentially leading to multiple sclerosis.

Molecular Mimicry - T cell response

• Microbial molecules activate self-reactive T cells.
• These T cells then react with and damage the body's own tissues

Molecular Mimicry - B cell response

• Foreign antigens activate T cells.
• T cells activate B cells to produce autoantibodies which attack self-antigens

More Examples of Molecular Mimicry

• Borrelia burgdorferi (Lyme disease) can cross-react with CD11a/CD18.
• Mycobacterium tuberculosis may cause rheumatoid arthritis in rats by reacting with HSP60

Abnormal Immune Responses (Lack of Regulatory Mechanisms)

• Neoplasms within lymphoid tissue can impair immune regulation leading to autoimmune disease.
• Defects in CD95 or its ligand, CD154, can lead to the development of autoimmune T and B cells.
• Mutations in genes for CD95 or CD154 can lead to autoimmune conditions in mice.
• A defect in AIRE (autoimmune regulator) can cause an autoimmune syndrome.

Autoimmune Diseases Induced by Virus Infection

• Reovirus infection may induce type 1 diabetes by producing autoantibodies against insulin.
• Coxsackie B virus related to type 1 diabetes development.
• Retroviruses may be associated with SLE in dogs.
• Molecular mimicry or bystander lymphocyte activation are possible methods for triggering autoimmunity due to virus infection

Mechanisms Underlying Autoimmune Disease Pathology

• Hypersensitivity type I involves IgE.
• Hypersensitivity type II involves IgG and IgM antibodies.
• Hypersensitivity type III involves antigen-antibody complexes.
• Hypersensitivity type IV involves T lymphocytes

Organ-Specific Autoimmune Diseases

Autoimmune Lymphocytic Thyroiditis

• Affects dogs and chickens (similar to human Hashimoto's thyroiditis).
• Autoantibodies target thyroglobulin or thyroid peroxidase.
• Autoantibodies block thyroxine (T4) and triiodothyronine (T3) production.
• Occurs often in young Dobermanns.
• Characterized by lymphocyte infiltration into the thyroid tissue, leading to hypothyroidism (underactive thyroid).
• Diagnosed after a significant portion of thyroid tissue is affected.

Insulin Dependent Diabetes Mellitus

• Loss of islet and beta cells in dog pancreas.
• Lymphocyte infiltration occurs in the pancreas.
• Antibody-dependent cell-mediated cytotoxicity (ADCC) is the primary mechanism driving damage.
• Cattle are affected by a more rare form of this disease.

Autoimmune Neurological Diseases- Equine Polyneuritis

• Rare disease in horses, sometimes linked to adenovirus type I infection.
• Autoantibodies against myelin protein P2 are involved.
• Involves sacral and coccygeal nerves.
• Symptoms include hyperesthesia progression to paralysis.
• Inflammation involves macrophages, lymphocytes, and plasma cells

Autoimmune Muscle Diseases – Myasthenia Gravis

• Affects multiple species (dogs, cats, humans)
• Disease of skeletal muscles.
• Fatigue and weakness after exertion are common symptoms.
• Caused by a lack of nerve impulse transmission to muscles due to autoantibodies targeting acetylcholine receptors.
• Frequently seen in breeds (Jack Russell Terrier and Fox terriers).
• Autoantibodies block acetylcholine receptors.
• Receptors may be further destroyed through complement fixation.
• Autoantibodies can target titin and ryanodine receptor proteins as well. This disease can be related to tumor growths.

Autoimmune Diseases of the Eye- Equine Recurrent Uveitis

• Features recurrent retinitis, uveitis, and vasculitis.
• Can lead to blindness
• Likely caused by autoantibodies targeting retinal proteins (e.g., retinoid and protein S).
• Th1 cell infiltration and fibrin and C3 deposition are present.
• Associated symptoms: High levels of anti-Leptospira interrogans antibodies.

Uveodermatological Syndrome

• Features include uveitis, retinitis, and skin depigmentation (especially whitening of hair).
• Macrophage infiltration of uveal tract is found.
• Skin damage can lead to detachment of retina and iris depigmentation.

Autoimmune Diseases of the Skin

• Can involve components such as hair follicles, keratinocytes, or basement membranes.
• Hypotrichosis can result if hair follicles are affected.
• Keratinocyte involvement leads to skin loosening and pemphigus development.

Alopecia Areata

• Characterized by hair loss in humans, dogs, cats, horses, and cattle..
• Hair loss is typically symmetrical.
• Autoantibodies targeting trichohyalin in hair follicles are implicated.

Blistering Diseases - Pemphigus Vulgaris

• Occurs in dogs, cats, horses and humans.
• Antibody-mediated reaction against desmoglein-3 (an adhesion molecule).
• Complex formation with autoantibodies activate protooncogene c-myc.
• Keratinocyte hyperproliferation and loss of cell adhesion molecules leading to blistering.

Pemphigus Foliaceus

• Skin blisters found in epidermal layers (in dogs, cats, goats, and horses).
• Autoantibodies target desmoglein-1.
• Skin separation (acantolysis) occurs in squamous cell desmosomes.

Autoimmune Disease of the Skin Basal Membrane- Bullous Pemphigoid

• Mostly seen in dogs.
• Similar to pemphigus vulgaris but involves skin basal membrane components.
• Predisposition in Dobermanns and Collies.
• Lesions are located on the border of skin basal membrane and dermis.
• Lesions develop under the epidermis.
• Autoantibodies against type XVII collagen and lamins 5 are involved.
• Infiltration of mononuclear cells and eosinophils can be observed.