Defects in innate immune components result in deficiency and diseases

In this article, I briefly describe how defects in innate immune components result in diseases and deficiency.

Table of Contents

Innate immune defects

Disorders in myeloid cells or in components of the complement activation pathways lead to innate immune defects. Many of these defects lead to lesser phagocytic cells or defective phagocytic processes. These processes may have defects at several stages, including cell motility, adherence to and phagocytosis of organisms, and intracellular killing by macrophages.

Chronic granulomatous disease

This disease impacts phagocytic function and occurs in two distinct forms. One of the two forms is the X-linked form, which happens in nearly 70% of patients. Other patients suffer from another form of the disease, which includes an autosomal recessive form. Granulomas are small masses of inflamed tissue. NADPH (nicotinamide adenine dinucleotide phosphate) oxidase enzyme helps phagocytes generate superoxide radicals and the reactive oxygen and nitrogen species that kill phagocytosed pathogens.

Chronic granulomatous disease happens due to the defective NADPH oxidase enzyme. Thus, patients with this disease suffer from infections with bacterial and fungal pathogens with excessive inflammatory responses that form granulomas. The disease is treated with antibiotics and antifungal compounds. According to the in vitro studies, treatment with IFN-γ enhances the phagocytosis of inflammation-inducing dead cells. IFN-γ acts like a macrophage activator and induces TNF-α with nitric oxide production. Enhancement of phagocytosis helps inhibit the formation of granulomas during inflammation in patients.

Leukocyte adhesion deficiency

Cell surface molecules of the integrin family of proteins act as adhesion molecules and are needed to ease cellular interaction. Three adhesion molecules, such as LFA-1, Mac-1, and gp150/95 have a common β chain and are variably present on different myeloid cells. These cell surface molecules can’t function due to a defect in the common β chain. This defect is called leukocyte adhesion deficiency, which affects the expression of all three molecules that use this chain. This defect causes susceptibility to infection with gram-positive and gram-negative bacteria with various fungi.

Impaired adhesion of leukocytes to the vascular endothelium reduces their ability to migrate to inflamed areas. This condition also weakens viral immunity due to defective T-B-cell interactions and the crucial role of LFA-1 in facilitating the attachment of cytotoxic T and NK cells to infected targets. The severity of LAD varies; some individuals succumb within a few years, while others live into their forties.

Rare autosomal recessive disease- Chediak-Higashi Syndrome

This syndrome is a rare autosomal recessive disease characterized by recurrent bacterial infections, faulty blood clotting, pigmentation, and neurologic function. Immunodeficiency is marked by depressed numbers of neutrophils (neutropenia), and less functioning of T cells, NK cells, and granulocytes. Chediak-Higashi syndrome results from a mutation in the lysosomal trafficking regulator (LYST) gene that causes defects in the LYST protein. The lysosome trafficking regulator (LYST) protein is important for transporting proteins into lysosomes. It also controls the size of the lysosome, its movement, and function. Disruption of lysosomes and melanocytes leads to enlarged organelles and defective transport functions.

Phagocytes that are affected produce giant granules, which is a diagnostic feature. However, they can’t kill engulfed pathogens and melanocytes can’t transport melanin. Some enlarged lysosome-like structures in platelets and nerve cells interfere with blood clotting and neurologic function. Defects are also observed in CTL and NK cell-mediated cytotoxicity.

Genetic susceptibility to mycobacterial diseases

A group of immunodeficiency disorders has recently been classified under a mixed-cell category due to their common feature of Mendelian (single-gene) inheritance, which increases susceptibility to mycobacterial diseases (MSMDs). Research into the genetic defects underlying MSMDs has shed light on the link between innate and adaptive immunity and emphasized the critical role of IFN-gamma in combating infections caused by mycobacteria, such as those responsible for tuberculosis and leprosy.

When an individual is affected with natural mycobacterial infection, pattern recognition receptors, such as TLR2 and TLR4 help macrophages in the lungs and dendritic cells in the draining lymph nodes to recognize these bacteria. Thus, cell migration happens to lymph nodes followed by activation and differentiation of antigen-presenting cells.

These activated antigen-presenting cells in the presence of a strong co-stimulation, produce significant amounts of IL-12 and IL-23, which can bind to their receptors on T helper cells and NK cells respectively. This results in the production of cytokines IL-17, IFN-γ, and TNF-α. In a self-reinforcing cycle, T_H cells differentiate into T_H1 cell types, which produce extra IFN- γ. IFN- γ binds to its receptor on antigen-presenting cells and induces a signaling cascade. STAT1 and Janus kinases involved in this signaling cascade increase phagocytosis. Optimal phagosome-lysosome fusion effectively kills engulfed bacteria. This T_H1 cell-mediated delayed-type hypersensitivity response is important for protection against Mycobacterium tuberculosis and M.leprae.

Mendelian susceptibility to mycobacterial diseases (MSMD)

Many primary immunodeficiencies that lead to increased susceptibility to mycobacterial infections result from mutations in genes encoding proteins involved in either the IL-12 activation and signaling pathway (such as NEMO, IL-12, the IL-12 receptor chain, and the associated TYK2 signaling molecule) or the IFN-γ pathway. The clearance of intravesicular infections relies on IFN-γ production by TH1cells, which is stimulated by IL-12 secretion from antigen-presenting cells (APCs) (figure 1). NEMO is a ubiquitin-binding protein that helps form the IKK complex. It is involved in innate immune signaling. NEMO protein is a part of the IKK complex in the NF-κB activation pathway. NF-κB is an essential transcription factor in activating immune responses with T and B cell activation. Thus, most mutations in the NEMO gene result in more immune defects and susceptibility patterns, which are observed in patients with MSMD.

Conclusion

Many innate immune defects lead to lesser phagocytic cells or defective phagocytic processes. Chronic granulomatous disease impacts phagocytic function and occurs in two distinct forms. Chronic granulomatous disease happens due to the defective NADPH oxidase enzyme. Thus, patients with this disease suffer from infections with bacterial and fungal pathogens with excessive inflammatory responses that form granulomas. The disease is treated with antibiotics and antifungal compounds.

Chediak-Higashi syndrome is a rare autosomal recessive disease characterized by recurrent bacterial infections, faulty blood clotting, pigmentation, and neurologic function. Immunodeficiency is marked by depressed numbers of neutrophils (neutropenia), and less functioning of T cells, NK cells, and granulocytes.

A group of immunodeficiency disorders has recently been classified under a mixed-cell category due to their common feature of Mendelian (single-gene) inheritance, which increases susceptibility to mycobacterial diseases (MSMDs). Many primary immunodeficiencies that lead to increased susceptibility to mycobacterial infections result from mutations in genes encoding proteins involved in either the IL-12 activation and signaling pathway (such as NEMO, IL-12, the IL-12 receptor chain, and the associated TYK2 signaling molecule) or the IFN-γ pathway.