AUTOIMMUNITY

conditions in which damage to organs and or tissues results from the presence of autoantibody or auto-reactive cells. ETIOLOGY: defect in mechanisms underlying self recognition POSSIBLE MECHANISMS: Loss of self-tolerance by B and/or T cells The response to self-reactive antigens The formation of neo-antigen Release of maturation antigen (sequestered antigen) Deficiency of T suppressor cells

GENERAL SIGNS OF AUTOIMMUNE DISEASES THAT MAY HAVE DIAGNOSTIC VALUE: Elevated serum gamma globulin Presence of diverse antibodies Depressed levels of serum complement Immune complexes in serum Depressed levels of Ts cells Lesions detected on biopsy resulting from deposition of immune complexes SYSTEMIC AUTOIMMUNE DISEASES SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) disease of the connective tissue expresses itself as a vasculitis it is an IMMUNE COMPLEX disease characterized by overproduction of AUTOANTIBODIES o (DNA-antiDNA complexes - most important of immune complex formed) ARTHRITIS - most common manifestation Also manifests itself by skin lesions, butterfly rash/RED WOLF (red rash across nose and cheeks)

CLINICAL TYPES OF AUTOIMMUNITY: 1. Organ-Specific lesions from damaged tissue and autoantibodies are directed towards a single target organ AUTOIMMUNE DISEASES Addisons Disease Acute disseminated encephalomyelitis Hashimotos thyroiditis Type 1 DM Goodpasteurs syndrome Graves disease Myasthenia gravis Autoimmune chronic active hepatitis Pernicious anemia Sjogrens syndrome Primary Biliary Cirrhosis Autoimmune Myocarditis Pemphigus vulgaris Bullous Pemphigoid Autoimmune rheumatic fever Autoimmune glomerulonephritis ANTIGENS/TARGET ORGANS OR CELLS Microsomal proteins of aderenal cells Basic protein of myelin Thyroglobulin, Microsomal antigen (thyroid peroxidase Islet cells of pancreas Type IV collagen of basement membrane TSH receptors Acetylcholine receptors Smooth muscles Gastric parietal cell antigens, intrinsic factor Salivary gland nucleolar antigens Mitochondria Striated cardiac muscle Epidermal antigens Skin basement region antigens Heart and joint tissue antigen Glomerular basement membrane

Laboratory Observations Most Striking Feature: Presence of Anti-Nuclear Antibodies (ANA) [although not diagnostic of SLE] LE Cell - PMN leukocyte with ingested LE body o (a homogenous cytoplasmic mass that often fills the cytoplasm of the phagocyte) often, LE bodies are not engulfed by neutrophils producing rosette formation LE FACTOR - a 7s IgG Antibody which reacts with DNP(deoxyribonucleoprotein) and complement o Hypocomplementemia o Hypergammaglobulinemia o Depletion of suppressor T cells (w/c allows overproduction of autoantibodies)

2. Systemic or Non-Organ Specific lesions from damaged tissue and autoantibodies are not confined to any organ. Sometimes called collagen vascular disease Rheumatoid arthritis - chronic, inflammatory joint disease with systemic involvement. Its hallmark feature is the presence of rheumatoid factors, an anti-IgG immunoglobulin that is produced by B cells and plasma cells in the synovial membrane. Systemic Lupus Erythematosus - chronic, inflammatory multi-organ disorder that predominantly affects young women of childbearing age.

"LE cell" test which has value only in demonstrating how the concept of autoantibodies work. The pink blobs are denatured nuclei. Here are two, with one seen being phagocytozed in the center by a PMN. This test is not nearly as sensitive as the ANA which has supplanted the LE cell test. Serologic Tests INDIRECT FLUORESCENT ANTIBODY TEST FOR DETECTION OF ANA Principle: Indirect Immunofluorescence Fluorescent Staining Patterns 1. HOMOGENOUS (solid, diffuse) anti-Histone, anti-ssDNA, anti-nucleoprotein (NP) typically seen in RA, drug-induced SLE, Sjogrens syndrome & MCTD

Lupus Erythematosus (LE) It was observed that when peripheral blood from a patient is incubated at 37OC for 30-60 minutes, the lymphocytes swell and extrude their nuclear material This nuclear material is opsonized by anti-DNA antibody and complement and is then phagocytosed by neutrophil. In this case, the cell is now called an LE cell.

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Anti-Centromere Antibody (ACA) highly selective for the CREST variant of scleroderma CREST- calcinosis cutis, Raynauds phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia CENTROMERE PATTERN VS. SPECKLED An especially fine Speckling with little background staining.

typical "homogenous" pattern of nuclear staining of a (+) ANA 2. PERIPHERAL/RIM (Ring, membranous,shaggy or thready) anti-dsDNA (in which the periphery of the nucleus reacts with px serum) assoc. with SLE in the active stage and Sjogren dse These are Crithidia organisms, whose sole purpose for existence is to serve as a substrate for the double stranded DNA test brightly fluorescing kinetoplasts indicative of a positive test. A positive double stranded DNA test strongly suggests a diagnosis of SLE

rim" pattern that is more characteristic of systemic lupus erythematosus (SLE) than other autoimmune diseases 3. SPECKLED (mottled, pepper-dots) occurs in the presence of Anti-Extractable Nuclear Ags [ENA - e.g. RNP, Sm, Ro (SSA), La (SSB)] Anti-RNP - not very specific but may be seen with an entity called MIXED CONNECTIVE TISSUE DSE (MCTD); also in SLE, RA, scleroderma, Sjogren Anti-Smith (Anti-Sm) - highly specific for patients with SLE Anti-Ro (SSA) and Anti La (SSB) primarily found in patients with SLE and Sjogren

closer view of the taut, shiny, inelastic skin with sclerodactyly. Note also the cheilosis at the corners of the mouth from riboflavin deficiency as a result of the malabsorbtion that can occur with scleroderma.

"speckled" pattern of antinuclear antibody test staining which is more characteristic of the presence of autoantibodies to extractable nuclear antigens (ENA), particularly to ribonucleoprotein PCNA (Proliferating Cell Nuclear Antigen) a unique variant of speckled pattern in Indirect Immunofluorescent Antibody test for detection of ANA that is said to be highly specific for SLE 4. NUCLEOLAR reflects Ab to nucleolar RNA (Anti-RNA) asso. with SCLERODERMA, Sjogrens, SLE and Raynauds phenomenon

A serious consequence of the "R" in the CREST syndrome (limited scleroderma) is seen here. The fingertips are blackened and additional portions of the hand purplish with early gangrenous necrosis from vasospasm with the Raynaud phenomenon ANTINUCLEAR ANTIBODY (ANA) VISIBLE METHOD Principle: Indirect Immunoenzyme Method

nucleolar pattern of staining with the ANA test that is more reminiscent of a view from the Hubble space telescope.

RHEUMATOID ARTHRITIS is an autoimmune disease causing chronic inflammation of the joints and periarticular tissue

complete cementing together (fusion) of the vertebrae, a process referred to as ankylosis. Ankylosis leads to loss of mobility of the spine. the autoimmune disease with the highest criteria for HLA-disease relationship; associated w/ HLA Ag B-27

Rheumatoid Factor (RF) group of immunoglobulins that interact specifically with the Fc portion of IgG molecules (antiantibodies) primarily, are of the IgM class

MISCELLANEOUS SYSTEMIC AUTOIMMUNE DISEASES PROGRESSIVE SYSTEMIC SCLEROSIS (SCLERODERMA) chronic dse of the connective tissue characterized by diffuse fibrosis involving the skin and several internal organs Raynauds phenomenon pain in the extremities when exposed to cold, Most common symptom SJORENS SYNDROME most often occurs secondary to RA, scleroderma, SLE manifestations: dry eyes (keratoconjunctivitis sica) dry mouth (xerostomia) ORGAN-SPECIFIC AUTOIMMUNE DISEASES Goodpastures syndrome Anti-glomerular basement membrane - kidneys Pernicious Anemia Anti-IF, Anti-parietal cells stomach Multiple Sclerosis Anti-myelin nervous system IDDM Anti-islet cells - pancreas Graves Dse Anti-thyroglobulin thyroid HAshimotoss thyroiditis - LATS (Long-Acting Thyroid Stimulating cells) thyroid ANCA (anti-neutrophil cytoplasmic antibody Wegeners granulomatosus - kidneys Myasthenia gravis anti-acetylcholine receptors muscles

However, the presence of RF alone is not enough for a diagnosis of RA. Although RF are not consistent with RA, the presence of (neutrophils or PMN) in inflamed joints is observed in all stages of the disease. These cells, as well as macrophages and other immune cells, compose the cellular infiltrate resulting in release of cytokines, radicals, and enzymes which participate in the destruction of a joint. RHEUMATOID FACTOR LATEX TEST Principle: REVERSE PASSIVE AGGLUTINATION

Two important Anti-cytoplasmic Antibodies 1. Anti-Smooth Muscle Antibody (anti-SMA) 2. high titer is strongly suggestive of chronic active hepatitis

Anti-Mitochondrial Antibody (AMA) useful marker for Primary Biliary Cirrhosis

ANTI-PHOSPHOLIPID Abs (APA) Synonymous with Anti-cardiolipin antibody also with Lupus Anticoagulant, an anti-phospholipid (that causes prolongation of APTT)

ANKYLOSING SPONDYLITIS is a form of chronic inflammation of the spine and the sacroiliac joints. Chronic inflammation in these areas causes pain and stiffness in and around the spine. Over time, chronic spinal inflammation (spondylitis) can lead to a