Autoimmune Diseases in Veterinary Species PDF

Autoimmunity Felix N. Toka, DVM, PhD, DSc., DACVM Objectives Define autoimmunity Describe the immunological basis for autoimmunity List and discuss the main autoimmune diseases in veterinary species  What is Autoimmunity? Immune reactivity involving either antibody-mediated (h...

Autoimmunity Felix N. Toka, DVM, PhD, DSc., DACVM Objectives Define autoimmunity Describe the immunological basis for autoimmunity List and discuss the main autoimmune diseases in veterinary species  What is Autoimmunity? Immune reactivity involving either antibody-mediated (humoral) or cell-mediated limbs of the immune response 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 (autoantigens) Autoimmune diseases may be either systemic or organ specific, depending on the distribution of the autoantigens that are recognized Various effector mechanisms are responsible for tissue injury in different autoimmune diseases Autoimmune diseases tend to be chronic, progressive, and self- perpetuating Principles of autoimmune disease Genetic conditions Among the genes that are associated with autoimmunity, the strongest associations are with MHC genes Abnormal display of self antigens increased expression and persistence of self antigens, structural changes in these antigens Inflammation or an initial innate immune response Infections or cell injury may elicit local innate immune reactions with inflammation Normal immune response as a result of cross-reactivity with an antigen related to a pathogen Certain autoimmune responses are physiological in nature e.g., Red blood cells (RBC) which must be eliminated after their life span. Phagocytosis plays a physiological role in this process. As RBCs age they shed CD47 from cell surface allows phagocytosis by macrophages. Immune response to hidden antigens in cells or tissues Many auto-antigens do not induce tolerance because they are hidden Lymphocytes become tolerant only to antigens that are presented earlier in the thymus In the case of extensive damage to tissue, hidden self antigens may appear in circulation and lead to production of auto antibodies (auto-Ab) “Certain auto-antigens are located at sites where there is no circulation of T cells” e.g., testes – new antigens appear in testes only after sexual maturity. Autoimmunization may occur when extensive damage is incurred in testes, releasing autoantigens into circulation (e.g., sperm  anti-sperm) Myocardial infarction leading to heart muscle damage may lead to formation of auto-Ab against heart muscle mitochondria Antigens generated through molecular configuration Completely new epitopes appear on normal proteins e.g., Rheumatoid factor (RF) RF are auto-Ab directed against other immunoglobulins When Ig binds an antigen, its configuration is altered leading to exposure of new epitopes, particularly in the Fc region These new epitopes may stimulate production of RF RF are produced in disease states where large amounts of antigen- antibody complexes are generated e.g., Systemic Lupus Erythematosus, SLE  Molecular mimicry common epitope shared between a pathogen and the host Infectious agents with antigens similar to autoantigens can induce an immune response that leads to production of Ab and T cells In such a case the produced antibodies and T cells not only eliminate the infectious agent, but they also react against self proteins e.g.,Trypanosoma cruzi encodes antigens that induce Abs that cross react with antigens in neurons and heart muscle in mammals Abs against Epstein Barr virus DNA polymerase cross-react with basic myelin protein  multiple sclerosis Molecular mimicry – T cell response Molecular mimicry – B cell response More examples Borrelia burgdorferi – cross-reacts with CD11a/CD18 (LFA-1) Mycobacterium tuberculosis – cross-reacts with HSP60 and may lead to rheumatoid arthritis in rats Mycoplasma hyopneumonia in swine or Mycoplasma mycoides in cattle – cross-reacts with auto-antigens in lungs Leptospira interrogans – cross reacts with auto-antigens in the eye  autoimmune recurrent uveitis in horses Abnormal immune responses Lack of regulatory mechanisms Neoplasms of the lymphoid tissue (thymus) – lead to destruction of certain immune regulatory elements and may lead to autoimmune disease e.g., Myasthenia Gravis Defects in expression of CD95 or its ligand CD154 allows development of autoimmune T or B cells e.g., in lpr mice – mutation in the gene encoding CD95 or in gld mice with a mutation in CD154 encoding gene a defect in AIRE (autoimmune regulator) – leads to an autoimmune syndrome involving endocrine organs, skin and other tissues  Autoimmune diseases induced by virus infection Infection with certain reoviruses may lead to type 1 diabetes in mice – production of auto-Ab against insulin Infection with Coxsackie B virus is associated with development of type 1 diabetes SLE in dogs may be associated with retrovirus type C or paramyxovirus infection The most probable mechanism of autoimmunity developement due to virus infection is molecular mimicry or by-stander activation (i.e., activation of non-antigen specific lymphocytes by cytokines) Mechanisms underlaying the pathology observed in autoimmune disease Hypersensitivity type I – mediated by IgE Hypersensitivity type II – mediated by IgG and IgM Hypersensitivity type III – mediated by Ag-Ab complexes Hypersensitivity type IV – mediated by T lymphocytes Organ-specific autoimmune diseases A result of inappropriate immune reaction against auto-antigens  Autoimmune Lymphocytic Thyroiditis (in humans Hashimoto’s disease) Occurs in dogs and chicken Develops due to formation of auto-Abs against thyroglobulin or thyroid peroxidase auto-Abs react and block thyroxin (T4) and triiodothyronine (T3)  mechanism of tissue damage – hypersensitivity type II Infiltration of the thyroid tissue with lymphocytes Disease occurs mostly in young Dobermanns Difficult to diagonize because the disease shows symptoms only after 75% of the thyroid tissue has been damaged  Symptoms - hypothyroidism  obesity, loss of hair coat, hyperpigmentation, pyoderma, low levels of T3 i T4 in serum Biopsy of the thyroid reveals lymphocyte infiltration and mostly confirms disease Auto-Ab detection with ELISA – auto-Ab levels rarely correlate with clinical disease Treatment – levothyroxine - maintenance of hormon level Similar disease occurs in leghorn white chicken  Insulin dependent diabetes mellitus (Type I diabetes) In dogs – occurs through loss of islets and β cells of the pancreas Lymphocyte infiltration in pancreas Mechanism of tissue damage – ADCC A rare disease in cattle  Autoimmune neurological diseases Equine polyneuritis A rare disease of horses May be associated with adenovirus type I infection Auto-Ab against myelin P2 protein Involves the sacral and coccygeal nerves Hyperesthesia followed by tail paralysis – loss of myelin, infiltration of macrophages, lymphocytes and plasma cells  Autoimmune muscle diseases Myasthenia gravis Occurs in dogs, cats and humans Disease of skeletal muscles Fatigue, weakness after mild exercise Results from lack of nerve impulse transmission to muscles due to deficiency of acetylcholine receptors  A frequent disease and hereditary in Jack Russel and Fox terriers auto-Abs against acetylcholine receptors Auto-Abs bind to receptors and block impulse transmission Receptors are later destroyed by complement fixation Also, auto-Ab against titin and ryanodine receptor protein  Predisposition is found German sheep dogs, Labradors, Daschunds, Abyssinian cats The disease may develop due tumor growth Abyssinian cat Autoimmune diseases of the eye Equine Recurrent Uveitis Recurrent retinitis, uveitis and vasculitis May lead to blindness Caused by auto-Ab against retinoid and protein S Th1 cell infiltration and deposition of fibrin and C3  Concurrently, a high level of anti-Leptospira interrogans antibodies is present Symptoms – lacrimation, photophobia and blepharism Molecular mimicry may play a critical role if additional infection occurs with Borrelia burgdorferii or Onchocerca cervicalis  Uveodermatological Syndrome Uveitis, retinitis and skin depigmentation including whittening of the hair coat Inflitration of lymphocytes, plasma cells and macrophages in the uveal tract  Macrophages are filled with melanin May lead to detachment of the retina and depigmentation of the iris Lesions may lead to complete blindness Corticosteroids may help with disease management Autoimmune diseases of the skin May involve hair follicles, keratinocytes or skin basement membrane If the disease involves hair follicles  hypotrichosis If the disease involves keratinocytes  loosening of skin and development of pemphigus  Alopecia areata Leads to loss of the hair coat in dogs, cats, horses, cattle and humans Loss of hair begins on the head and eventually spreads to the rest of the body Hair loss is symetrical Caused by auto-Ab against trichohyalin, a protein found in hair follicles http://www.vetnext.com/fotos/Telogen_effluvium_cow.jpg Blistering diseases Pemphigus vulgaris Occur in dogs, cats, horses and humans Caused by reaction of auto-Ab on desmoglein 3 (adhesion molecule) Complexes of desmoglein and auto-Ab activate protooncogen c-myc leading to hyperproliferation of keratinocytes Cells stop producing adhesion molecules leading to skin separation (acantolysis) - leads to formation of bullous in the skin https://encrypted-tbn3.gstatic.com/images Pemphigus foliaceus A disease similar to pemphigus vulgaris Lesions are located in the epidermis The disease occurs in dogs, cats, goats and horses Caused by auto-Ab against desmoglein 1 – adhesion molecule on squamous cell desmosomes http://www.askjpc.org/wsco/wsc/wsc95/images/c16c4gr1.j http://www.wpfelineclinic.com/CaseoftheMonth_08 pg 11_clip_image002.jpg Pemphigus foliaceus skin Subcorneal pustule in a Quarter Pemphigus Foliaceus in cat eruption on the ventral Horse with pemphigus foliaceous abdomen of a dog  Autoimmune disease of the skin basal membrane Caused by auto-Ab against components of the skin basal membrane - mostly in dogs Bullous pemphigoid The disease is similar to pemphigus vulgaris Predisposition in Dobermanns and Collies Lesions are located at the border of skin basal membrane and the dermis Lesions develop under the epidermis  Lesions are caused by auto-Ab reaction against type XVII collagen – a structure connecting keratinocytes and skin basal membrane, and auto-Ab against laminin 5 - a component of the skin basal membrane Deposition of IgA Infiltration of mononuclear cells and eosinophils http://www.vetnext.com/images/z/730678829 57%20399.gif https://s3.amazonaws.com/classconnection