B lymphocytes, T lymphocytes, and dendritic cells are involved in the pathogenesis of SLE. The pathogenesis of this systemic autoimmune disorder is characterized by the loss of tolerance to nuclear antigens, deposition of immune complexes in tissues, and multiorgan involvement.

Patients with SLE are known to produce multiple autoantibodies. There are two leading hypotheses, not mutually exclusive, as to why so many different antibodies develop. One hypothesis supports the belief that antibody-forming B lymphocytes are stimulated in a relatively nonspecific manner, so called polyclonal B cell activation. The second hypothesis is that the immune response in SLE is specifically stimulated by anti gens. The most compelling evidence in its favor is that the antibody molecules formed over time show evidence of the gene rearrangement and somatic mutation characteristic of an anti gen-driven response. Recent studies have suggested that the neutrophilic leukocyte activity is implicated in linked biochemical and cellular events. Findings suggest that in SLE, anti–self antibodies activate neutrophils that consequently release neutrophil extracellular traps (NETs) containing complexes of DNA and antimicrobial peptide. These complexes activate plasmacytoid dendritic cells, which leads to interferon-α release and perpetuation of inflammation and disease. In the future, NETs may serve as a biomarker or predictor of tissue damage in SLE.

Laboratory features of SLE are the presence of ANAs, immune complexes, decreased complement level, tissue deposition of immunoglobulins and complement, circulating anticoagulants, and other autoantibodies. The human antineutrophil cytoplasmic antibodies (ANCAs), described for the first time in 1982, are directed against antigenic components mainly present in primary granules of neutrophils. ANCAs are serologic markers of primary necrotizing systemic vasculitis, particularly in Wegener’s granulomatosis. In addition, these antibodies have a prognostic interest because, in most cases, their titer is correlated with clinical activity during the disease.

Cellular Aspects

SLE is a disease that results from defects in the regulatory mechanism of the immune system. Studies of the immunopathogenesis of lupus nephritis have demonstrated a variety of aberrations in T cell and B cell function. It is uncertain whether the disease represents a primary dysfunction of T cells or B cells, but alterations in function do occur. Lymphocyte subset abnormalities are a major immunologic feature of SLE. Among the T cell subsets, a lack of or reduced generalized suppressor T cell function and hyperproduction of helper T cells occurs. The formation of lymphocytotoxic antibodies with a predominant specificity for T lymphocytes by patients with SLE at least partially explains the interference with certain functional activities of T lymphocytes associated with SLE. Lymphocyto toxic antibodies are capable of destroying T lymphocytes in the presence of complement and coating peripheral blood T cells.

The regulation of antibody production by B lymphocytes, ordinarily a function of the subpopulation of suppressor T cells, appears to be defective in patients with SLE. Although no single cause can be implicated in the pathogenesis of SLE, patients exhibit a state of spontaneous B lymphocyte hyperactivity, with ensuing uncontrolled production of a wide variety of antibodies to host and exogenous antigens. Host response to some antigens, such as vaccination with influenza, is normal in many cases and the patient manifests a specific, well-controlled humoral immune response.

Humoral Aspects

 Circulating immune complexes are the hallmark of SLE. Patients with SLE exhibit multiple serum antibodies that react with native or altered self antigens. Demonstrable antibodies include antibodies to the following:

• Nuclear components

• Cell surface and cytoplasmic antigens of polymorphonuclear and lymphocytic leukocytes, erythrocytes, platelets, and neuronal cells

• Immunoglobulin G (IgG)

 SLE is characterized by autoantibodies to almost any organ or tissue in the body. These antibodies may not be specifically diagnostic for SLE. In addition, some may have pathologic significance.

Antibodies to host antigens, particularly nuclear antigens such as DNA, are the principal type of antibody produced in SLE. ANAs are a heterogeneous group of antibodies produced against a variety of antigens within the cell nucleus. ANAs may be found in diseases other than SLE (e.g., other rheumatic or nonrheumatic diseases), as well as in some patients undergoing specific drug therapy and in healthy older individuals. The absence of ANAs almost excludes the diagnosis of SLE unless the patient is being chemically immunosuppressed. ANA titers and specific anti-DNA antibodies fluctuate during the course of the disease. In some cases, a rise in titer may forewarn of an impending disease flare-up.

Antigens to which antibodies are formed are present on nucleic acid molecules (DNA and RNA) or proteins (histones and nonhistones) and on determinants consisting of nucleic acid and protein molecules. Drug-induced cases of lupus have a high incidence of antibodies to histones. Some of these anti bodies are directed against the double-stranded helical DNA (native DNA or dsDNA). The presence of anti–native DNA (anti-nDNA) antibodies was reported in 1957. High titers of dsDNA are seen primarily in SLE and closely parallel disease activity. Most SLE patients simultaneously demonstrate anti bodies to nucleoprotein and native DNA.

Other nuclear antibodies are directed at the determinants of single-stranded DNA (ssDNA). Antibody titers of 1:32 or higher indicate a substantial concentration of antibody in an autoimmune response. Antibody to the Smith (Sm) antigen, a nuclear acidic protein extractable by aqueous solution, is considered a marker for SLE because anti-Sm has been found almost exclusively in patients with SLE. The presence of anti-Sm is seen in 25% to 30% of patients with SLE, but it rarely occurs in those with other systemic rheumatic (collagen) diseases.

The ANA antideoxyribonucleoprotein (anti-DNP) gives rise to the LE cell, which is found in more than 90% of untreated patients with active SLE. SLE patients with serositis may form LE cells in vivo. The LE cell testing procedure is now an obsolete test. In SLE patients with serositis, LE cells formed in vivo may be observed in aspirate fluid (e.g., pleural fluid). LE cells have been shown to be an expression of the interaction between IgG antibodies and DNP. Anti-DNP is referred to as the LE serum factor.

Antibodies to the Robert (Ro) soluble substance–A (SS-A) nuclear antigens are associated with SLE skin disease and the neonatal SLE syndrome. Antibodies to the Lane soluble substance–B (SS-B) antigens are associated with SLE and with primary and secondary forms of Sjögren’s syndrome. Their presence with SS-A antigen in SLE indicates mild disease. When present as the only antibody, SS-B is associated with primary Sjögren’s syndrome.

Autoantibodies to RBCs result in hemolytic anemia and can be detected by the anti–human globulin (AHG) test. Mem brane-specific autoantibodies to neutrophils and platelets and autoantibodies to lymphocytes (cold-reactive type) are specific for SLE. Antibody titers correlate with disease activity.

Immunologic Consequences

 Antibodies combine with their corresponding antigens to form immune complexes. When the mononuclear phagocyte system is unable to eliminate these immune complexes completely, immune complexes accumulate in the blood circulation. These circulating immune complexes are deposited in the subendothelial layers of the vascular basement membranes of multiple target organs, where they mediate inflammation. The sites of deposition are determined in part by the following physiochemical properties of the particular antigens or anti bodies involved:

• Size

• Molecular configuration

• Immunoglobulin class

• Complement-fixing ability

After deposition, the immune complexes seem to initiate a localized inflammatory response that stimulates neutrophils to the site of inflammation, activates complement, and results in the release of kinins and prostaglandins. These activities become the basis of antibody-dependent, cell-mediated tissue injury.

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مواضيع ذات صلة

Treatment of Rheumatoid Arthritis

Juvenile Idiopathic Arthritis

Diagnostic Evaluation of Rheumatoid Arthritis

Immunologic Manifestations of Rheumatoid Arthritis

Signs and Symptoms of Rheumatoid Arthritis

Treatment of Systemic Lupus Erythematosus

Diagnostic Evaluation of Systemic Lupus Erythematosus

Signs and Symptoms of Systemic Lupus Erythematosus

Different Forms of Lupus

Renal Disorders

Neuromuscular Disorders

Autoimmune Hematologic Disorders