Immunoglobulins, also known as antibodies, are proteins produced by the immune system to identify and neutralize foreign invaders like bacteria and viruses. There are five main classes of antibodies: IgG, IgM, IgA, IgE, and IgD. While IgG and IgM are widely recognized for their roles in immune defense, IgD has historically been less understood. This article explores IgD’s structure, location, primary function in B cell activation, and its emerging roles in broader immune responses and disease.
Unveiling IgD: Identity and Location
Immunoglobulin D (IgD) is an antibody. Structurally, it is a monomeric, Y-shaped molecule composed of two identical delta (δ) heavy chains and two identical light chains. Its heavy chains possess a distinctive long hinge region, contributing to its flexibility and susceptibility to proteolytic degradation.
IgD’s primary location is on the surface of naive B lymphocytes, or B cells, where it functions as a B cell receptor (BCR) alongside IgM. This membrane-bound form is crucial for B cell development and is expressed once B cells exit the bone marrow and mature in peripheral lymphoid tissues. In contrast to other antibody types, IgD is found in very low concentrations in the bloodstream, typically accounting for less than 1% of total serum immunoglobulins. Its low serum concentration and short half-life differentiate it from other more abundant secreted antibodies.
The Primary Role in B Cell Activation
IgD’s most established function is its role as a B cell receptor (BCR) on the surface of naive B cells. Alongside IgM, IgD acts as a primary sensor for antigens, marking the initial stages of an adaptive immune response. When an antigen binds to the IgD receptor, it triggers a signaling cascade within the B cell, activating it.
Upon activation, the B cell undergoes proliferation. These activated B cells then differentiate into specialized cells. Some become antibody-producing plasma cells, which secrete large quantities of soluble antibodies.
Others undergo class switching, a process where they switch from producing IgM or IgD to other antibody types like IgG, IgA, or IgE, tailored for different immune functions. Additionally, some activated B cells develop into memory B cells, which quickly respond to future encounters with the same antigen, providing long-lasting immunity. The presence of IgD on naive B cells helps fine-tune their responsiveness, particularly to multimeric foreign antigens, while potentially attenuating responses to self-antigens.
Emerging Functions and Broader Influence
Beyond its well-defined role in B cell activation, research continues to uncover additional functions of IgD, particularly in mucosal immunity and its interactions with other immune cells. Secreted IgD, though present in low serum concentrations, enhances immune surveillance at mucosal surfaces, such as those found in the mouth, nose, and respiratory tract. This involves its ability to bind to microbial factors and pathogens, including certain bacteria and viruses.
IgD also interacts with mast cells and basophils, immune cells involved in allergic responses and inflammation. Secreted IgD binds to these cells, and when engaged by an antigen, it stimulates them to release immune-modulating substances, including pro-inflammatory cytokines like IL-1β and TNF, as well as B cell-stimulating factors such as IL-4, IL-5, and IL-13. While IgD binding activates these cells, it does not typically induce the degranulation and histamine release associated with IgE-mediated allergic reactions. This suggests a distinct regulatory role for IgD in modulating immune responses, potentially enhancing type 2 helper T cell-mediated immunity and influencing IgE production.
IgD’s Role in Health and Disease
The clinical significance of IgD is an area of ongoing study, with its levels and function sometimes implicated in various health conditions. One notable example is Hyper-IgD Syndrome (HIDS), a rare autoinflammatory disorder characterized by recurrent episodes of fever and inflammation. While elevated IgD levels were initially a key diagnostic feature, it is now understood that up to 20% of HIDS patients, particularly young children, may have IgD levels within the normal range. HIDS is linked to mutations in the mevalonate kinase (MVK) gene, which affects a metabolic pathway.
Beyond HIDS, IgD has been associated with certain autoimmune diseases and infections. Elevated serum IgD concentrations have been observed in some patients with autoimmune disorders like rheumatoid arthritis and lupus, and IgD may contribute to the production of pro-inflammatory cytokines in these conditions. Specific IgD antibodies have also been detected in response to various infections. However, the exact pathogenic role of IgD in many of these diseases is still being investigated, and its measurement often lacks definitive diagnostic value. Despite these complexities, research continues to explore IgD’s potential as a biomarker or therapeutic target in various clinical scenarios.