Autoimmune disease arises when the body mounts an immune response against itself due to failure to distinguish self tissues and cells from foreign (non-self ) antigens or loss of tolerance to self. This phenomenon derives from the activation of self-reactive T and B lymphocytes that generate cell-mediated or humoral immune responses directed against self antigens. The pathologic consequences of this reactivity constitute several types of autoimmune diseases. Autoimmune diseases are highly complex due to MHC genetics, environmental conditions, infectious entities, and dysfunctional immune regulation. Examples of such diseases include rheumatoid arthritis, psoriasis, systemic lupus erythematosus, multiple sclerosis, and insulin-dependent diabetes mellitus (type 1 diabetes). In rheumatoid arthritis, IgM antibodies (rheumatoid factors) are produced that react with the Fc portion of IgG and may form immune complexes that activate the complement cascade, causing chronic inflammation of the joints and kidneys. In systemic lupus erythematosus, antibodies are made against DNA, histones, red blood cells, platelets, and other cellular components. In multiple sclerosis and type 1 diabetes, cell-mediated autoimmune attack destroys myelin surrounding nerve cells and insulin-producing islet beta cells of the pancreas, respectively. In type 1 diabetes, activated CD4 TDTH cells that infiltrate the islets of Langerhans and recognize self islet beta cell peptides are thought to produce cytokines that stimulate macrophages to produce lytic enzymes, which destroy islet beta cells. Autoantibodies directed against the islet beta cell antigens are produced but do not contribute significantly to disease.
Immunodeficiency diseases result from inadequate function in the immune system; the consequences include increased susceptibility to infections and prolonged duration and severity of disease. Immunodeficiency diseases are either congenital or arise from extrinsic factors such as bacterial or viral infections or drug treatment. Affected individuals frequently succumb to infections caused by opportunistic organisms of low pathogenicity for the immunocompetent host. Examples of congenitally acquired immunodeficiency diseases include X-linked agammaglobulinemia, DiGeorge’s syndrome, and severe combined immunodeficiency disease (SCID) due to adenosine deaminase (ADA) deficiency.
X-linked agammaglobulinemia is a disease affecting males that is characterized by a failure of immature B lymphocytes to mature into antibody-producing plasma cells. These individuals are susceptible to recurrent bacterial infections, although the cell-mediated responses directed against viruses and fungi are preserved. DiGeorge’s syndrome is due to failure of the thymus to develop, resulting in diminished T-cell responses (TDTH, CTL), while the humoral response remains functional but does not benefit from T-cell help.
The ADA enzyme normally prevents the accumulation of toxic deoxy-ATP in cells. Deoxy-ATP is particularly toxic to lymphocytes, and it leads to death of T and B cells. Absence of the enzyme therefore results in SCID. Infusion of the purified enzyme (pegademase, from bovine sources) and transfer of ADA gene-modified lymphocytes have both been used successfully to treat this disease.
AIDS represents the classic example of immunodeficiency disease caused by extrinsic viral infection, in this instance the human immunodeficiency virus (HIV). This virus exhibits a strong tropism for CD4 T helper cells; these become depleted, giving rise to increased frequency of opportunistic infections and malignancies in infected individuals. AIDS is also characterized by an imbalance in Th1 and Th2 cells, and the ratios of cells and their functions are skewed toward Th2. This results in loss of cytotoxic T-lymphocyte activity, loss of delayed hypersensitivity, and hypergammaglobulinemia.