What is the pathophysiology of immunoglobulin A deficiency (IgAD)?

Updated: May 15, 2018
  • Author: Marina Y Dolina, MD; Chief Editor: Michael A Kaliner, MD  more...
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Answer

IgA is the second most common immunoglobulin in human serum (after IgG) and is the predominant immunoglobulin found in mucosal secretions. Most investigators conclude that more IgA is actually produced than any other immunoglobulin, since most of it is lost in secretions.

Structurally, IgA has 2 different forms. Most serum IgA is monomeric, while secretory IgA is a dimer that contains an extra protein chain referred to as the "secretory component;" it is this property that makes this unique immunoglobulin resistant to the proteolytic enzymes found in many human secretions. The IgA dimer and the J-chain that holds the 2 IgA monomers together are produced by B cells. The secretory component is added by the serous cells in the mucoserous glands that transport dimeric IgA and other polymeric immunoglobulins (ie, IgM) onto the mucous membranes; a fragment of the receptor/transport protein mediates this translocation. Deficiency of this "polymeric Ig receptor" has been reported, and knock-out mice have been developed in the laboratory. In this situation, the serum IgA level becomes elevated because the IgA cannot be transported out of the blood into the secretions.

Secretory IgA antibodies can neutralize viruses, bind toxins, agglutinate bacteria, prevent bacteria from binding to mucosal epithelial cells, and bind to various food antigens, thus preventing their entry into the general circulation. The activities of monomeric serum IgA are not fully understood. Dimeric serum IgA probably represents a kinetically defined pool that has not yet been transported.

IgAD is a primary immunodeficiency disease presumed to result from a failure of terminal differentiation in IgA-positive B cells. The development of B-lineage cells begins in the fetal liver. B-lineage cell development then transfers to the bone marrow, when it becomes the major hematopoietic organ. Pre–B cells become immature immunoglobulin M (IgM)–positive B cells and then migrate from the bone marrow to lymph node germinal centers. After leaving the bone marrow, the B cells mature and express immunoglobulin D (IgD) receptors, respond to antigens, and, with the help of T cells (CD4+), undergo proliferation and class switching and terminal differentiation into plasma cells. [12]

In germinal centers, antigen is presented by follicular dendritic cells with help from CD4+ T cells and stimulates B cells to proliferate and undergo somatic mutation and immunoglobulin class-switching. B cells that produce high-antigen affinity antibodies are selected to develop into plasma cells that produce different immunoglobulin isotypes (ie, IgM, IgG, IgA, or IgE) or become recirculating memory B lymphocytes. These processes are regulated by cell interaction molecules (eg, CD40 on B cells, CD40 ligand on activated T cells, ICOS, TACI-TACIR, etc), and cytokines (ie, interferon-gamma and interleukin [IL]–2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-13, IL-14, and IL-15) and their cell surface receptors. [12]

Most patients with IgAD have a normal number of B cells expressing surface IgA in their blood, but the amount of surface IgA on each B cell is markedly decreased. Based on animal studies, the failure of B cells to terminally differentiate into IgA-secreting plasma cells may be due to the lack of effects caused by co-stimulatory molecules or cytokines such as IL-4, IL-6, IL-7, or IL-10.


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