PATHO - Immune Disorders 2: Autoimmune Diseases

Immunologic Tolerance

Unresponsiveness to an antigen induced by exposure of lymphocytes to that antigen

Self-tolerance

Lack of responsiveness to one’s own antigens

Negative selection (Clonal deletion)

Immature T cells that express receptors for self antigens are eliminated by apoptosis

Receptor editing

Immature B cells that strongly recognize self antigens undergo antigen receptor gene rearrangement

Anergy

Lymphocytes that recognize self-antigens are rendered functionally unresponsive. Immature lymphocytes that recognize self-antigens in the central lymphoid organs like the thymus are killed by apoptosis. Also affects mature B-cells in the peripheral tissues

IL-10, TGFB

Inhibit lymphocyte activation and effector functions

IL-2, FOXP3

Development and maintenance of regulatory T cells

Apoptosis

T-cells that recognize self-antigens may receive signals that promote their death by?

Mitochondrial pathway

Unopposed Bim (proapoptotic protein)

Death receptor pathway

Fas-FasL system

Immune-Priviledged Sites

Eye, testism brain. Tissues that do not communicate with blood and lymph. Self antigens in these tissues fail to elicit immune responses and are essentially ignored by the immune system. Antigens introduced to these sites tend to elicit weak or no immune responses

Autoimmunity

Equilibrium between lymphocyte activation and tolerance. Immune reactions against self-antigens due to a loss of self-tolerance

Susceptibility Genes

May contribute to the breakdown of self tolerance. Many autoimmune diseases are associated with different class II HLA alleles

PTPN22

Non-HLA gene that is most frequently implicated in autoimmune diseases

Environmental Triggers

Promote activation of self-reactive lymphocytes. Upregulation of costimulators of APCs → breakdown of anergy, activation of T cells, specific for self antigens. Molecular mimicry – antigens in microbes may share amino acid sequences with self antigens

Rheumatic heart disease

Antibodies vs. streptococcal proteins cross-react with myocardial proteins

Infections

Promote lymphocyte entry into tissues, activation of self-reactive lymphocytes, inflammation, and tissue damage

UV Radiations

Causes cell death and may lead to exposure of nuclear antigens which elicit pathological immune responses such as in the case of systemic lupus erythematosus (SLE). This is the proposed mechanism for the association of lupus flares with exposure to sunlight

Autoimmune disease

An immune reaction specific for some self-antigen. The immune reaction must not be secondary to tissue damage. No other well-defined cause of the disease

Autoimmune diseases

They are chronic, often with relapses, remissions, and exacerbations, leading to progressive damage.

Female predilection

Many autoimmune diseases are more common in women than men, likely due to hormonal effects and genes on the X chromosome.

Familiar prevalence

There is an increased likelihood of developing autoimmune diseases within families, either the same disease or different types.

Effect of hormones and unknown X-chromosome genes

What are two key underlying factors proposed to explain female predominance in autoimmune diseases?

Systemic Lupus Erythematosus

An autoimmune disease involving multiple organs characterized by a vast array of autoantibodies, particularly antinuclear antibodies (ANAs), in which injury is caused mainly by deposition of immune complexes and binding of antibodies to various cells and tissues

Antinuclear antibodies (ANAs)

Indirect immunofluorescence pattern suggests the type of antibody present

Anti-Smith

What is the most specific ANA’s in SLE patients?

Indirect immunofluorescence assay (IFA)

The most widely used method for detecting ANAs. Serum is layered on cultured HEp-2 cells and binding is detected with an anti-Ig antibody labeled with a fluorochrome

Homogenous Nuclear Pattern

Antibodies to chromatin, histones, dsDNA. Common in SLE

RIM (Peripheral Nuclear Pattern)

Antibodies to dsDNA, nuclear envelope proteins. More characteristic of SLE

Speckled Pattern

Antibodies to non-DNA nuclear elements: Smith, RNP, SS-A, SS-B

Centromeric Pattern

Pattern that is often seen in patients with systemic sclerosis

Nucleolar Pattern

Antibodies to RNA. Most often seen in patients with systemic sclerosis

Antiphospholipid Antibodies

Antibodies against the phospholipid-β2-glycoprotein complex bind to cardiolipin antigen → false (+) syphilis serology tests. “Lupus anticoagulant”

HLA-DQ locus

Autoantibody production in SLE

Type III (Immune Complex-Mediated) Hypersensitivity

What type of hypersensitivity does SLE fall under?

Secondary antiphospholipid antibody syndrome

Thromboses, recurrent spontaneous miscarriages, cerebral or ocular ischemia

Butterfly rash

Immune complex deposition at the dermoepidermal junction. Urticaria, bullae, maculopapular lesions, ulcerations. Sunlight exposure

Libman-Sacks endocarditis

Nonbacterial verrucous endocarditis. Warty deposits on either surface of any heart valve

Subacute Cutaneous Lupus Erythematosus

Widespread, superficial, nonscarring rash. Mild systemic symptoms. Anti-SS-A antibodies

Drug-Induced Lupus Erythematosus

Hydralazine, procainamide, isoniazid, D-penicillamine, anti-TNF therapy. Development of anti-histone antibodies

Sjorgen Syndrome

A chronic disease characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) resulting from immunologically mediated destruction of the lacrimal and salivary glands

Sicca syndrome

Primary form of Sjorgen Syndrome. Secondary form is more common – most commonly associated with rheumatoid arthritis

Sjorgen Syndrome

Lymphocytic infiltration and fibrosis of lacrimal and salivary glands → decreased tears and saliva. CD4+ Th cells, B cells, plasma cells. (+) Rheumatoid factor in 75% (with or without rheumatoid arthritis). (+) ANA in 50-80%. Antibodies against SS-A (Ro) and SS-B (La)

Keratoconjunctivitis, Xersostomia, Enlargement of salivary gland

What are the clinical features of Sjorgen Syndrome?

Keratoconjunctivitis

Inflammation of the cornea and conjunctiva. Blurring of vision, burning and itching, accumulation of secretions

Xersostomia

Dryness of mouth. Difficulty in swallowing solid food, decreased ability to taste, cracks and fissures in the mouth

Sjorgen Syndrome

Lacrimal and salivary glands. Exocrine glands lining the respiratory tract, GIT, vagina. Periductal and perivascular lymphocytic infiltrates +/- germinal centers. Hyperplasia of ductal epithelial cells. Inflammation, erosion, ulceration of the corneal epithelium

Systemic Sclerosis (Scleroderma)

Chronic inflammation thought to be the result of autoimmunity. Widespread damage to small blood vessels. Progressive interstitial and perivascular fibrosis in the skin and multiple organs. Excessive fibrosis in the skin and may involve other various organs

Limited Scleroderma

A type of sclerodoma with skin involvement in the fingers, forearms, face: late visceral involvement

Diffuse Scleroderma

A type of sclerodoma with widespread skin involvement, rapid progression, early visceral involvement

Calcinosis, Raynaud phenomenon, Esophageal dysmotility, Sclerodatcyly, Telengiectasia

What is the CREST syndrome?

Raynaud phenomenon

Numbness, tingling of fingers. Dysphagia, esophageal hypomotility. Atony, dilatation due to destruction of the esophageal walls

Anti-Scl 70

Antibody against DNA topoisomerase I; highly specific. Pulmonary fibrosis, peripheral vascular disease

CREST

What is the antricentromere antibody in systemic sclerosis?

Systemic Sclerosis

Diffuse sclerotic atrophy of skin. Increased collagen in the dermis. Atrophy of dermal appendages. Thickening of walls of arterioles and capillaries

Mixed Connective Tissue Disease

Disease with clinical features that overlap with those of SLE, systemic sclerosis, and polymyositis. Antibodies to UI ribonucleoprotein. Synovitis (finers), Raynaud phenomenon, myositis, renal involvement. May evolve into classic SLE or systemic sclerosis

Allografts

Grafts from the same species

Xenografts

Grafts from one species to another

Hyperacute

What pattern of graft rejection is this: preformed antibodies for antigens on graft endothelial cells. Within minutes. Cyanotic, mottled, anuric?

Acute

What pattern of graft rejection is this: T cells (acute cellular rejection) andantibodies (acute humoral rejection) activated by alloantigens in the graft. Within days/weeks?

Chronic

What pattern of graft rejection is this: T-cells and alloantibodies. Over months or years. Progressive loss of function. Refractory to most therapies?

Amyloidosis

Proteins with the propensity to aggregate to form fibrils and deposit extracellular tissues, causing tissue damage and functional compromise

Amyloid

Not a single chemical entity (thought to resemble starch – amylose). Continuous nonbranching fibrils. Stacks of protofilaments with β-pleated structure

Abnormal folding of proteins

What is the pathogenesis of amyloidosis?

Amyloid light chain protein

Complete Ig light chains, amino-terminal fragments of light chains, or both

AL Amyloidosis

Abnormal amounts of a single Ig → M spike on serum electrophoresis. Free λ > κ light chains: Bence Jones protein. Secreted by monoclonal plasma cells. Most common form of systemic amyloidosis

ATTR Amyloidosis

Composed of transthyretin. ATTRwt - normal transthyretin produce deposits in the heart. Usually M, >70 y/o. Genetic mutation or aging of the protein. AATRv - variant transthyretin produce deposits in various organs

ATTRwt

Normal transthyretin produce deposits in the heart

AATRv

Variant transthyretin produce deposits in various organs

AA Amyloidosis

Amyloid-associated protein. From proteolysis of serum amyloid-associated protein (SAA; protein made by the liver). SAA is increased as part of the acute phase response. Systemic distribution. RA, IBD, heroin use. Renal cell ca, Hodgkin lymphoma