Interferon-γ receptor 1 and 2 mutations

Interferon-γ receptor 1 and 2 mutations refer to genetic alterations in the components of the interferon-γ (IFN-γ) receptor complex, which plays a crucial role in the immune system's defense mechanisms against infections, particularly those caused by mycobacteria, such as tuberculosis. The IFN-γ signaling pathway is essential for the activation of macrophages, cells that are pivotal in controlling bacterial and viral infections. Mutations in the genes encoding the interferon-γ receptor 1 (IFNGR1) and interferon-γ receptor 2 (IFNGR2) can lead to a spectrum of immune deficiencies, ranging from mild to severe, depending on the nature of the mutation.

Genetics and Pathophysiology

The IFNGR1 and IFNGR2 genes are located on the chromosomes 6 and 21, respectively. Mutations in these genes can be either autosomal recessive or autosomal dominant, affecting the expression and function of the receptor components. Autosomal recessive mutations often lead to a complete absence of receptor expression, resulting in a severe form of Mendelian Susceptibility to Mycobacterial Diseases (MSMD), characterized by a high susceptibility to infections by weakly virulent mycobacteria and other intracellular pathogens. Autosomal dominant mutations, on the other hand, typically result in partial receptor deficiencies, leading to a milder disease phenotype.

Clinical Manifestations

Individuals with mutations in IFNGR1 or IFNGR2 genes may present with recurrent, severe infections by mycobacteria and other intracellular pathogens from an early age. These infections can include, but are not limited to, tuberculosis, BCG vaccine complications, and non-tuberculous mycobacterial infections. The severity and frequency of these infections are directly related to the extent of the receptor deficiency.

Diagnosis

Diagnosis of IFN-γ receptor mutations involves a combination of clinical evaluation, laboratory testing, and genetic analysis. Laboratory tests may show an absence or reduced levels of IFN-γ receptor expression on the surface of immune cells. Genetic testing is crucial for identifying specific mutations in the IFNGR1 and IFNGR2 genes.

Treatment

Management of patients with IFN-γ receptor mutations focuses on the prevention and treatment of infections. This may include prophylactic antibiotics, vaccination against common pathogens, and prompt treatment of infections. In severe cases, hematopoietic stem cell transplantation (HSCT) has been used as a curative approach, aiming to restore a functional immune system.

Conclusion

Interferon-γ receptor 1 and 2 mutations represent a significant challenge in the field of immunology and infectious diseases, highlighting the importance of the IFN-γ signaling pathway in human immunity. Advances in genetic testing and therapies offer hope for improved management and outcomes for affected individuals.