Numerous immunodeficiency diseases are caused by mutations affecting molecules involved in lymphocyte activation (Fig. 1).

Fig1. Congenital immunodeficiencies associated with defects in lymphocyte activation and effector functions. Congenital immunodeficiencies may be caused by genetic defects in the expression of molecules required for antigen presentation to T cells, T or B lymphocyte antigen receptor signaling, helper T cell activation of B cells and macrophages, and differentiation of antibody-producing B cells. A, Examples showing the sites at which immune responses may be blocked.

Defects in B Cell Responses

Defective antibody production may result from abnormalities in B cells or in helper T cells.

 • The X-linked hyper-IgM syndrome is characterized by defective B cell heavy-chain isotype (class) switching, so immunoglobulin M (IgM) is the major serum antibody, and by deficient cell-mediated immunity against intracellular microbes. The disease is caused by mutations in the X chromosome gene encoding CD40 ligand (CD40L), the helper T cell protein that binds to CD40 on B cells, dendritic cells, and macro phages and thus mediates T cell–dependent activation of these cells . Failure to express functional CD40L leads to defective germinal center reactions in T cell–dependent B cell responses, so there is poor humoral immunity with little Ig isotype switching and no affinity maturation. In addition, there is defective T cell–dependent macrophage activation in cell-mediated immunity. Boys with this disease are especially susceptible to infection by Pneumocystis jiroveci, a fungus that survives within phagocytes in the absence of T cell help. An autosomal recessive form of hyper-IgM syndrome with a similar phenotype to that seen in the X-linked disease is observed in individuals with mutations in CD40. Another autosomal recessive form of hyper-IgM syndrome in which there are humoral abnormalities but no defect in cellular immunity is seen in individuals with mutations affecting the enzyme activation-induced deaminase (AID), which is involved in B cell isotype switching and affinity maturation .

• Genetic deficiencies in the production of selected Ig isotypes are quite common. IgA deficiency is believed to affect as many as 1 in 700 people but causes no clinical problems in most patients and sinus, lung, and intestinal infections in a minority. The defect causing these deficiencies is not known in a majority of cases; rarely, the deficiencies may be caused by mutations of Ig heavy-chain constant (C) region genes.

• Common variable immunodeficiency (CVID) is a heterogeneous group of disorders that are characterized by poor antibody responses to infections and reduced serum levels of IgG, IgA, and sometimes IgM. The underlying causes of CVID include defects in various genes involved in B cell maturation and activation or in T-B cell collaboration. Some patients have mutations in genes encoding receptors for B cell growth factors or costimulators that play a role in T cell–B cell interactions. Patients have recurrent infections, autoimmune disease, and lymphomas. 

Defective Activation of T Lymphocytes

A variety of inherited abnormalities may interfere with T cell activation.

 • The bare lymphocyte syndrome is a disease caused by a failure to express class II major histocompatibility complex (MHC) molecules, as a result of mutations in the transcription factors that normally induce class II MHC expression. Recall that class II MHC molecules display peptide antigens for recognition by CD4+ T cells and this recognition is critical for maturation and activation of the T cells. The disease is manifested by a profound decrease in CD4+ T cells because of defective maturation of these cells in the thymus and poor activation of the cells in peripheral lymphoid organs.

• Rare cases of selective T cell deficiency are caused by mutations affecting various signaling pathways or cytokines and receptors involved in differentiation of naive T cells into effector cells. Depending on the mutation and the extent of the defect, affected patients show severe T cell deficiency or deficiency in particular arms of T cell–mediated immunity, such as in Th1 responses (associated with nontuberculous mycobacterial infections) and Th17 responses (associated with fungal and bacterial infections). These defects have revealed the importance of various path ways of T cell activation, but these are rare disorders.

• Hemophagocytic lymphohistiocytosis (HLH) syndromes are characterized by systemic, sometimes life-threatening, activation of immune cells including macrophages, usually in response to infections. Many cases of HLH occur as a manifestation of genetic dis orders in which cytotoxic CD8+ T cells and NK cells are unable to kill virus-infected target cells. These include patients with mutations in the gene encoding perforin as well as mutations in genes that encode proteins involved in granule exocytosis. These mutations result in persistent infections, usually viral, and excessive production of IFNγ by T cells and NK cells, which in turn causes excessive macrophage activation. Some of these highly activated macrophages ingest red blood cells, giving the syndrome its name. 

مواضيع ذات صلة

Clinical Features of HIV Infection and AIDS

Pathogenesis of AIDS

Congenital Immunodeficiencies: Defects in Lymphocyte Maturation

Congenital Immunodeficiencies: Defects in Innate Immunity

Congenital (Primary) Immunodeficiencies

Neuroimmunology: Interactions Between the Immune and Nervous Systems

Disorders of Neutrophils

Cell Surface Receptors

Sepsis

Acute Inflammation

Diseases Caused by T Lymphocytes

Etiology, Examples, and Therapy of Immune Complex–Mediated Diseases