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Systemic Lupus Erythematosus (SLE)

The manifestations are protean, and there is no characteristic or pathognomonic finding. Instead, this disease is diagnosed by finding suggestive serologic and clinical findings. Findings may include:

Skin rash - malar or discoid Sensitivity to light (photodermatitis) Serositis - inflammation of serosal surfaces along with effusions Glomerulonephritis - the worst problem with SLE Cytopenias - anemia, leukopenia, thrombocytopenia Antinuclear antibody - rim pattern, anti double stranded-DNA and anti-Smith autoantibodies are most specific for SLE Arthralgias, myalgias Vasculitis - anywhere: CNS, skin, kidney, etc Decreased serum complement - especially C1q Thrombosis - in arteries or veins

Genetic factors: tends to run in families; association with HLA Dr-2 and Dr-3; more common in young women (especially African-American). Drugs can produce "drug-induced" SLE: list includes procainamide, hydralazine, isoniazid, d-penicillamine. Discoid lupus erythematosus (DLE): a benign disease with skin involvement; ANA positive in only a third (but some of these go on to SLE).

Scleroderma (Progressive Systemic Sclerosis, PSS)

Characterized by excessive fibrosis in a variety of tissues from collagen deposition by activated fibroblasts. About 75% of cases are in women, mostly middle aged. Patterns of disease include: Limited scleroderm, or CREST syndrome: the benign form of PSS, serologically suggested by the presence of anti-centromere antibody

C = Calcinosis in skin and elsewhere R = Raynaud's phenomenon, sensitivity to cold E = Esophageal dysmotility from submucosal fibrosis S = Sclerodactyly from dermal fibrosis T = Telangiectasias

Diffuse scleroderma: the worst form of PSS; Scl-70 (anti-DNA topoisomerase I) antibody shows specificity for this form. It may include all of the findings with CREST, but additionally has renal findings: arterial intimal thickening and proliferation (hyperplastic arteriolosclerosis) leading to malignant hypertension with arterial fibrinoid necrosis, thrombosis, and renal infarction. Half of diffuse PSS patients die from renal disease. The lungs in this form of scleroderma may have diffuse alveolar fibrosis leading to honeycomb fibrosis

Morphea: this is skin fibrosis only

Characterized by inflammation of skeletal muscle with weakness. Sometimes it is associated with a skin rash (hence, dermatomyositis). It is seen in ages 40-60, but also in ages 5-15, mostly in women. Some of these patients have Jo-1 antibody. Inflammation in polymyositis is mainly mediated by cytotoxic CD8 cells. In dermatomyositis, mainly antigen-antibody complexes produce a vasculitis in muscle and skin. Some adults (1020%) develop cancer.

Sjogren's Syndrome
Characterized by dry eyes and dry mouth as a result of lacrimal and salivary gland involvement by lymphocytic infiltration, fibrosis, and destruction mediated by CD4+ cells helping antibody production, of which anti-SS-A and anti-SS-B are the most specific. Most patients are middle to older age women. Lacrimal and salivary gland inflammation of any cause (including Sjogren's) is called Mikulicz's syndrome.


X-linked Agammaglobulinemia of Bruton
Congenital agammaglobulinemia (Bruton's Disease) results from a genetic defect on the long arm of X chromosome, so that males are primarily affected (inheritance occurs in an X-lined recessive pattern). The mutations affect production of a tyrosine kinase (Bruton tyrosine kinase, or btk) active in early pre-B cells which diminishes their maturation and leads to virtual absence of all immunoglobulin classes. Infants are observed to have multiple infections with bacterial organisms (Hemophilus, Staphylococcus), particularly in skin and lung. Agammaglobulinemia is the result of absent B-cells, but T-cell mediated immunity is intact. If affected persons survive, many will develop autoimmune diseases.

Common Variable Immunodeficiency

This is a heterogenous group of disorders with an incidence of 1 per 100,000 that can involve both humoral and cell mediated immunity. Though there are normal numbers of circulating B lymphocytes, there is impaired secretion of one or more immunoglobulin isotypes, usually IgG or IgA. A selective abnormality of T cell activation, as demonstrated by decreased synthesis of interleukins (IL 2, 4, and 5) has been identified. Patients may have impaired gastrointestinal mucosal immunity. Another variant results from either a decrease in CD4 cells or an increase in CD8 cells. Also occuring is a variant resulting from the presence of T and B lymphocyte autoantibodies. At least two of the three main serum immunoglobulin isotypes are decreased. Persons with CVID are prone to recurrent bacterial infections, particularly sinusitis, bronchitis, pneumonia, bronchiectasis, and otitis. Bordatella pertussis infections occur in childhood. Viral infections are uncommon, though recurrent herpes simplex with eventual herpes zoster is an exception. Giardiasis is common. Half of CVID cases are diagnosed before age 21, but in some cases complications do not develop until adolescence or adulthood.

There is an increased incidence of autoimmune diseases, particularly hemolytic anemia, thrombocytopenia, and pernicious anemia. In about two thirds of cases, normal numbers of circulating B lymphocytes are present. There is a decrease in immunoglobulins, generally in all classes, more often IgG and IgA, but sometimes only of IgG.

DiGeorge Syndrome
The DiGeorge syndrome (or sequence) is a field defect of third and fourth pharyngeal pouch development in utero during organogenesis in the first trimester of pregnancy. A specific deletion on the long arm of chromosome 22 has been implicated. Anatomic structures that may be aplastic or hypoplastic include the thymus, parathyroid glands, great vessels, and esophagus. DiGeorge syndrome may be further subclassified as complete, in which there is almost total absence of thymic tissue, or as partial, in which there is only a decrease in thymic tissue Complete DiGeorge syndrome is characterized by normal levels of circulating immunoglobulin, though in some cases serum IgE is increased and IgA is decreased. However, affected children have markedly decreased numbers of circulating T lymphocytes, making them susceptible to fungal and viral infections. Children with partial DiGeorge syndrome have only a slight decrease in peripheral T lymphocytes and have increased infections, but with less frequency and with less severity than children with the complete form. Accompanying aplasia of parathyroid glands can lead to lifethreatening hypocalcemia that may appear soon after birth.

Severe Combined Immunodeficiency (SCID)

SCID results from different defects with different inheritance patterns, but all demonstrate some degree of failure in development of both humoral and cell-mediated immunity. The major variants of SCID include:

An X-linked form is due to a mutation on the long arm of the X chromosome which produces a defective gamma chain of the interleukin-2 receptor (cytokine receptor). Lacking an intact interleukin receptor renders early lymphocytes incapable of normal differentiation and development to functional T and B cells in response to growth factors. This form accounts for about 60% of cases. Autosomal recessive inheritance linked to a lack of the enzyme adenosine deaminase (ADA) leads to about 35 to 40% of cases. The ADA enzyme is involved in purine metabolism, and its deficiency results in production of metabolites toxic to lymphocytes

There tends to be a greater decrease in cell mediated immunity than in humoral immunity. Normal or increased numbers of B lymphocytes may be present with the X-linked form, but these cells still do not function properly. There is very little serum IgG and virtually no IgM or IgA. Infants develop Candida skin rashes and thrush, persistent diarrhea, severe respiratory tract infections with Pneumocystis carinii and Pseudomonas soon after birth, and failure to thrive after 3 months of age. Severe viral can occur. Maternal T lymphocytes crossing the placenta may produce graft versus host disease

Wiskott-Aldrich Syndrome

An X-linked recessive pattern is seen because the defective gene is located on the short arm of the X chromosome (Xp11.23). The immunodeficiency is accompanied by thrombocytopenia and eczema. Circulating platelets are markedly decreased. T lymphocytes exhibit cytoskeletal disorganization and loss of microvilli by electron microscopy, and they express little CD43 by immunohistochemical staining. There is usually a normal level of serum IgG, along with a decrease in IgM, but often an increase in both IgA and IgE. The initial onset of disease in early childhood is accompanied by recurrent bacterial infections, particularly to encapsulated bacteria such as Streptococcus pneumoniae, with development of pneumonia, meningitis, and septicemia. Later, failure of T lymphocyte function may predispose to recurrent herpetic infections and to Pneumocystis carinii pneumonia. A bleeding problem may result from the severe thrombocytopenia.

A genetic defect is present on the long arm of chromosome 11 which predisposes to chromosome breakage and rearrangement, particularly on chromosomes 7 and 14, leading to a high risk for neoplasia and a marked sensitivity to radiation. This disorder is quite rare and has an autosomal recessive pattern of inheritance. There is a triad of progressive cerebellar ataxia, mucocutaneous telangiectasias, and recurrent respiratory tract infections with a variety of bacterial and fungal organisms. Immunoglobulin deficiencies, particularly IgA and/or IgE, may be present, though serum IgM is usually elevated. The symptoms usually begin between 9 months and 2 years of age.

Selective IgA Deficiency

About 1 in 600 persons of European descent has a virtual lack of circulating IgA as well as secretory IgA which, in most cases, results from failure of the IgA type of B lymphocytes to transform into plasma cells capable of producing IgA or from impaired survival of IgA producing plasma cells. Some patients may have deficiencies in IgG subclasses 2 and/or 4, while IgG subclasses 1 and 3 are increased. Some patients go on to develop common variable immunodeficiency, suggesting that there is a similar defect in B cell maturation and function. Some affected patients are at increased risk for respiratory, gastrointestinal, and urinary tract infections, most often bacterial, and diarrhea is common. More severely affected persons may even have a sprue-like illness with malabsorbtion. Atopy, as demonstrated by asthma, can be present. Concomitant autoimmune diseases, particularly systemic lupus erythematosus and rheumatoid arthritis, can be present. About half of IgA deficient persons develop anti-IgA antibodies of the IgE type, so that transfusion of blood products containing serum with normal IgA levels leads to severe systemic anaphylaxis.

Other Primary Immunodeficiency Disorders

Deficiencies of other components of the immune system are uncommon. Some of the best known are:

Complement component deficiencies: C2 deficiency carries a risk for development of autoimmune disease. C3 deficiency is associated with recurrent bacterial infections. Chediak-Higashi syndrome: A rare autosomal recessive disorder in which peripheral blood neutrophils, monocytes, and lymphocytes contain giant cytoplasmic granules and patients have leukopenia, making them susceptible to bacterial and fungal infections of skin, mucous membranes, and respiratory tract Chronic granulomatous disease: neutrophils and monocytes lack the enzyme NADPH oxidase which is needed to generate intracellular oxidants that destroy phagocytosed infectious organisms, particularly catalase-positive agents such as Staphylococcus aureus, Candida, and Aspergillus, so that chronic infections are common