Loss or improper function of a part of the immune system results in immunodeficiency disorders. When impairment of the immune system is due to a genetic defect, the disorder is termed ‘primary immunodeficiency’. Immune deficiency results in repeated infections, often with otherwise innocuous organisms and in cases of severe immune defects, such infections can be life threatening.
Immune deficiencies are generally classified into cellular and humoral or antibody deficiencies. While antibody deficiencies can be treated with supplemental immunoglobulin, cellular defects are much more difficult to treat and tend to be characterized by deep seated infections with intracellular organisms such as mycobacteria, fungi and viruses. Cellular defects leading to increased susceptibility to mycobacterial disease form a unique subset of immune deficiencies that predominantly affect the interferon gamma (IFNγ) and the interleukin-12 (IL-12) pathways that are key mediators of immunity to intracellular infection.
The immune response to mycobacterial infection involves a complex interplay of the innate and adaptive immune systems. Mycobacteria are phagocytosed by professional antigen presenting cells, such as macrophages and dendritic cells and survive and replicate within the phagosome. Infected macrophages produce cytokines including TNF-α and IL-12 and present mycobacterial antigens to CD4 and CD8 T cells, thereby driving the adaptive immune response. Upon antigen recognition and activation by IL-12, T cells are activated and produce key cytokines such as IFNγ that acts upon macrophages to further activate them. This cycle, the IL-12 – IFNγ cytokine loop, is critical to the control of mycobacterial infection (Figure 1).
Figure 1. The immune response to mycobacterial infections.
Mendelian Susceptibility to Mycobacterial Disease (MSMD) is caused by mutations in genes responsible for the various immune functions of T cells and phagocytes (monocytes, macrophages, dendritic cells) that are necessary for control of mycobacterial infections. Defects in these genes can lead to varying degrees of susceptibility to a variety of nontuberculous mycobacterial species of low pathogenicity, M. bovis BCG, as well as other intracellular pathogens such as Salmonella typhimurium, viruses such as Varicella-Zoster virus and fungi such as Cryptococcus sp. and Histoplasma sp. These genetic defects may be inherited in an autosomal dominant (AD), autosomal recessive (AR) or X-linked manner.
The clinical presentation varies with the extent to which the mutation affects protective immune processes. For example, AR defects of the interferon gamma receptor (IFNγR) that lead to complete loss of surface expression of the receptor, abrogate the interferon gamma response entirely. Similarly, AR mutations of STAT1 (Signal Transducer and Activator of Transcription 1), a molecule downstream of IFNγR and responsible for the transcription of IFNγ responsive genes, also lead to a complete loss of the IFNγ response. Patients with these AR mutations of STAT1 and IFNγR are extremely susceptible to nontuberculous mycobacterial infections and tend to develop severe, disseminated disease in early childhood. Partial defects of the IFNγR that retain residual activity result in less severe infections that may be localized rather than disseminated. Mutations of the IL-12 receptor β1 chain (one of the two components of the IL-12R) or mutations of the IL-12p40 subunit of the functional IL-12 p70 molecule lead to less severe infections. Although relatively rare, mutations of IFNγR, IL-12R and IL-12p40 are observed more frequently than mutations in other IFNγ-related genes. These include: (1) interferon regulatory factor 8 (IRF-8) that plays a major role in antigen processing and presentation by mononuclear phagocytes, (2) interferon-stimulated gene 15 (ISG15) that induces production of IFNγ by Natural Killer (NK) and T cells and (3) STAT1. Genes that contribute to increased susceptibility to mycobacterial infection, but that are outside of the IFNγ-IL-12 loop include (1) GATA2 (MonoMac syndrome), a transcription factor that drives development of myeloid cells, (2) Nuclear factor-kappa-B essential modulator (NEMO) that activates NF-kB and thereby downstream genes that mediate essential immune functions, and the X-linked CYBB gene that encodes gp91phox, a component of the NADPH complex that mediates neutrophil and monocyte oxidative burst. Although rare, mutations in these genes predispose individuals to mycobacterial infections. The various genetic defects identified to date that are associated with chronic, often disseminated, mycobacterial infections are listed in Table 1.
Table 1. MSMD related genes
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Laboratory diagnosis and treatment
Laboratory diagnosis of IFNγR and IL-12R mutations includes analysis of surface expression of the receptors by flow cytometry along with demonstration of function by analysis of STAT1 and STAT4 phosphorylation, following stimulation with IFNγ and IL-12 respectively. Undetectable IL-12p40 and functional IL-12p70 as well as reduced IFNγ production by lymphocytes is seen in patients with mutations of the IL12Rβ1 or IL-12. Although phenotypic and functional analysis is helpful and can support diagnosis, sequencing is required for a definitive diagnosis for these and other genetic mutations listed in Table 1. Treatment of MSMD depends on the severity of infection. Severe cases such as AR complete IFNγR or STAT1 deficiency, MonoMac syndrome or NEMO mutations may be corrected by bone marrow transplant. Milder defects are treated with anti-mycobacterial therapy and supplemental IFNγ.
Vijaya Knight, MD, PhD, Director, Immunology & Beryllium Laboratories, National Jewish Health, Denver, CO
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