Discuss the pathologic, clinical, and laboratory findings with systemic lupus erythematosus. (<250 words)

SLE is an autoimmune disease that is more frequently seen in younger persons, particularly blacks and females. The clinical presentation may consist of a "butterfly" malar skin rash, often with arthralgias, fever, and myalgias. The HLA types DR2 or DR3 are often associated with SLE. The etiology is unknown, but there appears to be a polyclonal B-cell activation with production of antibodies to "self" antigens in tissues.

Most of the pathologic manifestations result from a type III hypersensitivity reaction from antigen-antibody complexes. These immune complexes are deposited in many areas, but particularly in skin, serosal surfaces, and vessels. The immune complexes activate complement and lead to inflammation. This results in the common complication of glomerulonephritis, which can lead to renal failure. Serosal inflammation can produce pericarditis or pleuritis with effusions. Cerebral vasculitis can produce seizures or acute psychosis.

Important laboratory findings include a positive antinuclear antibody test. More specific tests for SLE include the anti-Sm (ribonucleoprotein) and anti-double stranded DNA. Serum complement is often decreased. Antibodies directed against blood components can lead to anemia, leukopenia, and thrombocytopenia.

Discuss the major clinical and pathologic findings associated with scleroderma (progressive systemic sclerosis). (<250 words)

Progressive systemic sclerosis is an autoimmune disease primarily seen in women and in middle age. The etiology is unknown, but the disease appears to be mediated by T-cell lymphocytes directed against connective tissue so that there is a response of collagenous fibrosis in multiple organs. This is manifested in the skin clinically by tightening and loss of folds or wrinkles. Sensitivity to cold (Raynaud's phenomenon) may be a presenting complaint, and sometimes arthritis or myositis. There may be malabsorption from gastrointestinal involvement, and esophageal dysmotility is a frequent problem. Chronic lung disease with pulmonary fibrosis can occur.

The diffuse form of this disease is characterized by renal involvment from progressive thickening of the arteries as a result of autoimmune injury to endothelial cells with stimulation of fibroblast activity. This leads to hypertension, which in a small number of cases is severe (malignant) with fibrinoid necrosis, hemorrhage, and microinfarctions. The benign form of this disease is known as the CREST syndrome because of the findings of calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias. CREST patients have limited or late involvment of visceral organs and rarely have renal problems.

Diagnosis is aided by finding of positive antinuclear antibody test, often with a nucleolar pattern. More specific tests include the antibody Scl-70, directed against DNA topoisomerase, which is most characteristic of the diffuse form, and also anticentromere antibody, which most commonly appears with the CREST syndrome.

Discuss the causes, complications, and diagnosis of amyloidosis. (<250 words)

Amyloidosis is the term given to the appearance of an extracellular, proteinaceous material called amyloid which is composed of non-branching fibrils organized into a beta-pleated sheet structure by electron microscopy. By light microscopy amyloid appears as an amorphous, homogenous, pink material that can be stained by Congo red and has apple-green birefringence under polarized light. Immunofluorescence can be used to detect amyloid composed of light chains.

There are several forms. The most common in the U.S. is the AL form of amyloid derived from light chains of immunoglobulin, usually as a result of increased light chain production from multiple myeloma, and light chains may also appear in the urine. The AA form of amyloid is derived from serum amyloid-associated protein and appears in persons with chronic inflammatory disease conditions such as rheumatoid arthritis or tuberculosis. In both cases, macrophages probably are involved in processing the amyloid protein, though it is not clear exactly why amyloid appears. Amyloid may also appear with familial Mediterranean fever, with medullary carcinoma of the thyroid, and with aging. With aging, transthyretin protein contributes to the appearance of cardiac amyloid, while beta-2 amyloid protein is found in cerebral blood vessels of patients with Alzheimer's disease.

Significant deposition of amyloid can lead to organ dysfunction. Cardiac amyloidosis can lead to heart failure and arrhythmias. Renal amyloidosis can lead to proteinuria and to renal failure. Other organs such as the liver and spleen may also be involved.

Discuss the clinical and pathologic findings associated with common variable immunodeficiency. (<250 words)

Common variable immunodeficiency can present in young adults, or sometimes in children. Males and females can both be affected. There is a decreased production of immunoglobulins in all classes, or sometimes just IgG. Two-thirds of patients have normal numbers of circulating B-cells. However, maturation into plasma cells is defective, so immunoglobulin production is impaired, but T-cell function remains intact, so fungal and viral infections are uncommon. This can be due to an intrinsic B-cell abnormality, suppression of B-cell activation by inhibitory cytokines from T-cells, autoantibodies to B-cells, or lack of T helper cell function. No specific inheritance pattern is present, but a similar genetic defect may lead to the appearance of selective IgA deficiency relatives of affected persons.

Clinical manifestations include recurrent upper respiratory and pulmonary infections, otitis media, and diarrhea. Bacterial infections with Streptococcus pneumoniae, Hemophilus influenzae, and Staphylococcus aureus are frequent. Gastrointestinal problems include recurrent infections with Giardia lamblia, malabsorption, and pernicious anemia. This can lead to weight loss in adults or failure to thrive in children. Lymphoid hyperplasia may lead to generalized lymphadenopathy. There is an increased incidence of autoimmune diseases such as Grave's disease and thyroiditis. There is an increased risk for development of lymphoma. Therapy consists of administering immunoglobulin and prompt diagnosis and treatment of infections.

Discuss the clinical and pathologic findings associated with mixed connective tissue disease. (<250 words)

Mixed connective tissue disease (MCTD) is an autoimmune disease with features that overlap systemic lupus erythematosus (SLE), progressive systemic sclerosis (PSS), and polymyositis (PM). Most patients are women (the female to male ratio is 4:1) in middle age. The antinuclear antibody (ANA) test is usually positive, but with a distinctive speckled pattern of immunofluorescence, unlike the rim pattern of SLE or the nucleolar pattern of PSS. A more specific finding is a high titer ribonucleoprotein (RNP) assay. Unlike SLE, the Smith and ds-DNA antibodies are usually absent. Patients may also have a polyclonal gammopathy from non-specific B-cell activation. If a significant myositis is present, the creatine kinase may be elevated. In some cases, rheumatoid factor may be present.

Clinical findings similar to SLE include skin rashes, arthralgias, and myalgias, but unlike SLE renal complications are uncommon with MCTD. Circulating immune complexes with vasculitis can account for these findings. Findings that overlap PSS include esophageal dysmotility, pulmonary hypertension, Raynaud's phenomenon, and sclerodactyly. As in PM, there can be proximal muscle weakness. Weight loss and anemia are additional findings similar to other autoimmune diseases. Patitents with MCTD generally have a better prognosis than PSS or SLE patients, and many respond to corticosteroid therapy if their disease is severe.

Discuss pathologic findings, including laboratory testing, that can help to diagnose and distinguish patients with autoimmune diseases. (<250 words)

Example 1:

Use of the antinuclear antibody (ANA) test is helpful to screen for autoimmune diseases. Type III hypersensitivity with immune complex deposition leads to many manifestations, with similar signs and symptoms in many of these diseases, including malaise, skin rashes, arthralgias, and myalgias. A higher titered ANA suggests more serious or active disease. The patterns of immunofluorescence with the ANA may help to distinguish some autoimmune diseases. A rim pattern is more specific for systemic lupus erythematosus (SLE), a nucleolar pattern for systemic sclerosis (SS), and a speckled pattern for mixed connective tissue disease (MCTD). The non specific homogenous pattern is most often seen. If the ANA test is positive, additional autoantibody tests can be used to further differentiate autoimmune diseases. The anti-double stranded DNA and anti-Smith antibody tests have specificity for SLE. Anti-DNA topoisomerase I antibody positivity suggests the diffuse form of SS, while an anti-centromere antibody is more typical for the milder CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) syndrome of SS. Elevated ribonucleoprotein (RNP) suggests MCTD, which has features of SLE, SS, and polymyositis. In this latter condition, the Jo-1 antibody can be positive. Pathologic findings more typical of SLE include glomerulonephritis and vasculitis. In SS, pulmonary fibrosis and renal hyperplastic arteriolosclerosis can be seen. Polymyositis can have an inflammatory myopathy and increased serum creatine kinase.

Example 2:

Autoimmune diseases may arise from several different immunologic mechanisms. Type II hypersensitivity leads to anti-receptor antibody mediated diseases. These include myasthenia gravis, with antibody to acetylcholine receptor, which leads to generalized muscular weakness. Grave's disease, with antibody to TSH receptor, results in stimulation of thyroid epithelial cells with increased thyroid hormone production and hyperthyroidism. In Goodpasture's syndrome, an antibody to basement membrane is produced, resulting in pulmonary damage with hemoptysis and/or renal glomerular damage with hematuria.

Cross-reactive antibodies may form following infection. Group A beta-hemolytic streptococcal infections may result in formation of antibodies to components of the streptococcal organisms that cross react with components of heart and kidney. This can cause acute rheumatic fever involving the heart or glomerulonephritis that involves the kidney. T-cells cross reacting with viral antigens may play a role in the development of type 1 diabetes mellitus.

Type III hypersensitivity reactions are typical for the collagen vascular diseases such as systemic lupus erythematosus. In these diseases, antibodies are directed against "self" antigens, and antigen-antibody complexes are formed. These complexes can deposit in tissues, particularly where a basement membrane is present, such as in blood vessels, glomeruli, synovium, mesothelium, and skin. The inflammatory reaction that results includes complement activation and tissue destruction, with the result that vasculitis, glomerulonephritis, arthritis, pleuritis, and skin rashes can be seen.

Discuss pathologic findings, including laboratory testing, that can help to diagnose and distinguish patients with primary immunodeficiency diseases. (<250 words)

Example 1:

Infections that are recurrent, multiple, and severe in infants and children suggest a possible inherited immunodeficiency. Either cell-mediated immunity, humoral immunity, or both may be involved. Bruton's agammaglobulinemia, an X-linked disorder in which there is lack of maturation of B-cells to immunoglobulin secreting plasma cells, leads to bacterial infections in infancy as maternally acquired antibodies are lost. Selective IgA deficiency, the most common primary immunodeficiency (1:700 persons), is much less severe, and marked by increased sinopulmonary infections and diarrhea from lack of mucosal IgA. Common variable immunodeficiency generally presents in adults with deficiency in one or more immunoglobulin classes, usually IgG. Most patients have normal numbers of B cells, but they fail to mature. In severe combined immunodeficiency (SCID), both T and B cell function are deficient. In most cases of SCID there is X-linked inheritance of a stem cell defect with lack of IL-2 receptor so that T cells do not develop properly and B cells do not function either; in other cases of SCID there is an autosomally recessive inherited lack of adenine deaminase that results in cytotoxicity for lymphocytes. Patients with SCID present early in life with multiple viral, bacterial, fungal, and parasitic infections. DiGeorge syndrome presents in infancy with increased viral and fungal infection due to a lack of T cells. In this disorder, the thymus is partially or nearly absent. The parathyroid glands may also be lacking, and hypocalcemia can result.

Example 2:

Laboratory testing for primary immunodeficiencies may include a CBC with differential to determine if there is a decrease in circulating lymphocytes, as may be seen with DiGeorge syndrome or severe combined immunodeficiency (SCID). Further characterization of lymphocytes as T and B cells can be done by flow cytometry. This may help to distinguish patients with common variable immunodeficiency, in which normal numbers of B cell circulate, but immunoglobulins are diminished. In SCID, T cells are diminished but B cells are present, though not completely functional. Just total protein and albumin values from a chemistry panel may indicate hypogammaglobulinemia. The globulins can be further quantified by class--IgG, IgM, and IgA, and subclass. This can help to distinguish patients with selective IgA deficiency, which may be asymptomatic in adults, but who are at risk for a transfusion reaction. Immunoglobulin levels can distinguish Bruton's agammaglobulinemia, an X-linked condition presenting in infancy in which virtually all immunoglobulins are absent. Testing of neutrophil function with a nitroblue tetrazolium test helps to determine if chronic granulomatous disease in infants is present. Complement components can be measured to determine whether there are deficiencies of specific components such as C2 or C3 that increase the risk for autoimmune diseases such as SLE. In fact, the risk for autoimmune diseases and for malignancies (carcinomas and lymphomas) is increased with primary immunodeficiencies because of lack of immune function and immune surveillance.

Describe the features and the pathogenesis of type I hypersensitivity. (<250 words)

Type I hypersensitivity is an immediate type of immune response that can occur because prior exposure to an antigen, called an allergen, leads to production of increased amounts of IgE antibody, called sensitization. This antibody becomes attached to mast cells and basophils via Fc receptors. When the antigen is encountered again, the IgE is crosslinked and triggers degranulation with release of powerful primary mediators such as histamine that, within minutes, produce vasodilation and bronchial smooth muscle contraction. Production of secondary mediators such as prostaglandins and leukotrienes occurs over the next hour or more via the arachidonic acid pathway. Cytokines are released that attract additional inflammatory cells, particularly eosinophils and neutrophils. These mediators and cytokines result in anaphylaxis. There are two types of anaphylaxis. Localized anaphylaxis can occur when an allergen, such as ragweed pollen, induces edema and erythema in just a localized area such as the nasal cavity. Other examples include food allergies, with hives or diarrhea, asthma, and latex glove allergy with skin rash. Antihistamines help to treat the symptoms. Systemic anaphylaxis occurs with more generalized cytokine release and can be life-threatening from laryngeal edema, pulmonary bronchoconstriction, and hypotension with shock. The best examples of systemic anaphylaxis are allergy to bee sting or to penicillin. Emergent administration of epinephrine may be needed to treat systemic anaphylaxis.