Search

Abstract Background Innate immune deficiencies can impair both cellular and humoral immune responses. In contrast, other immune functions may appear normal, leading to increased susceptibility to specific pathogens, such as severe viral infections or Mendelian Susceptibility to Mycobacterial Disease (MSMD). Studying these deficiencies is essential for understanding the pathophysiology of these infectious diseases. Main body While primary immunodeficiencies (PIDs) generally cause vulnerability to multiple infections, innate immunodeficiencies increase susceptibility to specific pathogens, despite normal immune responses to others. Patients with these deficiencies show normal immunoglobulins and lymphocyte subpopulations, complicating diagnosis. This review highlights genetic susceptibility to mycobacteria, pneumococci, herpes simplex virus, and candidiasis, emphasizing recognizing this subset of PIDs. Conclusion This review highlights the diverse spectrum of genetic mutations contributing to defects in innate and intrinsic immunity, including Mendelian susceptibility to mycobacterial disease (MSMD), chronic mucocutaneous candidiasis, and predispositions to invasive bacterial and viral infections. Identifying key mutations in pathprovideh such as TLR3, IFN signaling, and IL-17A/F immunity provides valuable insights into the pathogenesis of these conditions. Our findings underscore the need for early genetic diagnosis and targeted interventions, particularly in regions with high undiagnosed cases, to reduce the morbidity and mortality associated with defects in innate and intrinsic immunity.

Abstract Background Mycobacteria include ubiquitous species of varying virulence. However, environmental and individual-specific factors, particularly host genetics, play a crucial role in the outcome of exposure to mycobacteria. The first molecular evidence of a monogenic predisposition to mycobacteria came from the study of Mendelian susceptibility to mycobacterial disease (MSMD), a rare inborn error of IFN-γ immunity conferring a selective susceptibility to infections even with low virulent mycobacteria, in patients, mostly children, without recognizable immune defects in routine tests. This article provides a global and updated description of the most important molecular, cellular, and clinical features of all known monogenic defects of MSMD. Results Over the last 20 years, 19 genes were found to be mutated in MSMD patients (IFNGR1, IFNGR2, IFNG, IL12RB1, IL12RB2, IL23R, IL12B, ISG15, USP18, ZNFX1, TBX21, STAT1, TYK2, IRF8, CYBB, JAK1, RORC, NEMO, and SPPL2A), and the allelic heterogeneity at these loci has led to the definition of 35 different genetic defects. Despite the clinical and genetic heterogeneity, almost all genetic etiologies of MSMD alter the interferon gamma (IFN-γ)-mediated immunity, by impairing or abolishing IFN-γ production or the response to this cytokine or both. It was proven that the human IFN-γ level is a quantitative trait that defines the outcome of mycobacterial infection. Conclusion The study of these monogenic defects contributes to understanding the molecular mechanism of mycobacterial infections in humans and to the development of new diagnostic and therapeutic approaches to improve care and prognosis. These discoveries also bridge the gap between the simple Mendelian inheritance and complex human genetics.

Abstract Background DiGeorge syndrome (DGS), caused by a deletion del(22)(q11.2q11.2), is the most frequently observed microdeletion syndrome. There is a vast clinical heterogeneity in DGS, and several studies suggested also heterogeneity of clinical signs and phenotypic appearance to be related to ethnic differences. Here, clinical characteristics of 72 patients with molecular diagnosed deletion del(22)(q11.2q11.2) derived from different countries from Europe, America, Africa, and Asia are summarized and compared. Results Unless ethnic differences, the expected major clinical signs were present in all cases. Frequent clinical manifestations found in this study were congenital heart disease with 68% (49/72), followed by dysmorphic features found in 61% (44/72); neurodevelopmental disorders were present in 43% (31/72) and thymus hypoplasia/aplasia in 32% (23/72). However, clinical features of the patients appeared/were recognized at different times during their lives. Within the group, under 2 years predominated heart disease, dysmorphic features, and hypocalcemia and/or hypoparathyroidism. In the group older than 2 years, the following combination of clinical findings was most frequent: dysmorphic features, congenital heart disease, intellectual disability, and immunological disorders. In the eight cases detected prenatally, abnormal sonographic findings were the major clinical signs (cardiovascular malformations and renal malformations). Conclusions Despite the heterogeneous nature of the sample analyzed, a number of clinical findings could be highlighted to be useful for the clinical delineation of this DGS. Interestingly, diagnostic indicators may vary depending on the age at diagnosis. Finally, apparent differences in DGS patients from different regions seem to be rather due to applied test systems than to real differences in patients from different ethnicities.