Autoimmunity and immunodeficiency are two states of immune disorders, while one represents a hyperimmune state and the other a hypoimmune state. Antibodies play an important role in both immunodeficiency diseases and autoimmune diseases.
A significant proportion of primary immunodeficiency diseases include humoral deficiency. Humoral deficiencies range in severity from complete deficiencies observed in diseases such as X-linked or autosomal recessive agammaglobulinemias and certain severe combined immune deficiencies to milder specific antibody deficiencies. In addition, the molecular abnormalities and pathogenesis for many of the antibody deficiencies remain unknown.
Patients with X-linked agammaglobulinemia (XLA) have mutations in the gene that encodes tyrosine kinase (Btk or Bruton’s tyrosine kinase). Defects in the Btk gene affect the early stages of B-cell differentiation and no mature B cells are produced. Common variable immunodeficiency (CVID), also called acquired hypogammaglobulinemia, adult-onset hypogammaglobulinemia, or dysgammaglobulinemia, is a heterogeneous group of disorders involving both B-cell and T-cell immune function, the predominant manifestation of which is hypogammaglobulinemia. CVID is characterized by recurrent bacterial infections (and rarely by virus infections), decreased serum Ig levels, and abnormal antibody responses. IgA deficiency is one of the most common antibody deficiencies and is defined as a serum IgA concentration of less than 7 mg/dL with normal serum IgM and IgG levels. IgA deficiency may be found in association with other immune abnormalities, including ataxia-telangiectasia and IgG subclass deficiencies. Individuals affected LRBA (lipopolysaccharide-responsive and beige-like anchor) deficiency show reduced levels of at least 2 Ig isotypes (IgM, IgG, or IgA) and suffer from recurrent infections, hepatosplenomegaly, chronic pulmonary and gastrointestinal disorders, as well as autoimmune conditions including immune thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA), and autoimmune enteropathy.
In autoimmune diseases, mechanisms that regulate the balance between recognition of pathogens and avoidance of self-attack are impaired. The role of B lymphocytes in autoimmunity has been associated largely with the capacity to produce self-damaging antibodies. These autoreactive antibodies bind self-antigens and can interfere with normal cellular functions as well as harness immune effector mechanisms to generate autoimmune pathology. The presence of auto-antibodies is a common feature of autoimmune diseases, and a large number of serum antibodies are directed against functional structures of the cell (nucleic acids, nuclear molecules, receptors, or other functional cell components). They not only play a central role in diagnosis and classification but may also be involved in tissue damage. There are many antibody-dependent autoimmune syndromes such as immune thrombocytopenia (ITP), systemic lupus erythematosus (SLE), myasthenia gravis, rheumatoid arthritis (RA), Graves’ disease, and multiple sclerosis (MS).
One of the best-established pathogenic effects of autoantibodies is the cytotoxic destruction of cells by cell surface binding and lysis. In this process, complement activation and/or antibody-dependent cell-mediated cytotoxicity (ADCC) are the most common pathways of destruction. Immune complex-mediated damage is another important pathogenic mechanism. SLE is a typical example of damage by the immune complex. In RA, rheumatoid factor-IgG complexes are also a component of synovial damage. Another mechanism includes binding to extracellular molecules (such as in the antiphospholipid antibody syndrome) where autoantibodies are directed against β-2-glycoprotein I in plasma.
Fig.1 Autoimmunity is a result of a multi-orchestrated immune response. (Wang, 2015)
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