Recent Advances in Primary Immunodeficiencies: Identification of Novel Genetic Defects and Unanticipated Phenotypes

Abstract

Primary immunodeficiencies (PIDs) have traditionally been defined according to their immunologic phenotype. Far from being concluded, the search for human genes that, when mutated, cause PID is actively being pursued. During the last year, four novel genetic defects that cause severe combined immunodeficiency and severe congenital neutropenia have been identified. At the same time, the immunologic definition of primary immunodeficiencies has been expanded by the recognition that genetic defects affecting innate immunity may result in selective predisposition to certain infections, such as mycobacterial disease, herpes simplex encephalitis, and invasive pneumococcal infections. Studies of genetically determined susceptibility to infections have recently shown that immunologic defects may also account for novel infectious phenotypes, such as malaria or leprosy. Finally, a growing body of evidence indicates that primary immunodeficiencies may present with a noninfectious clinical phenotype that may be restricted to single organs, as in the case of atypical hemolytic uremic syndrome or pulmonary alveolar proteinosis. Overall, these achievements highlight the importance of human models, which often differ from the corresponding animal models. (Pediatr Res 65: 3R-12R, 2009) F or many years, "classical primary immunodeficiencies," in which broad susceptibility to infections is due to mutations of a single gene, have represented a unique model to identify gene products that play a key role in initiating, maintaining, or regulating immune function. The study of diseases such as severe combined immunodeficiency (SCID), X-linked agammaglobulinemia (XLA), chronic granulomatous disease (CGD), and many more has led to better understanding of the mechanisms that are involved in development and function of T and B lymphocytes and of phagocytic cells. Since 1952, when unique susceptibility to recurrent infections was linked to lack of serum gammaglobulins (1), and for more than 30 y, primary immunodeficiencies (PID) were mainly defined in terms of clinical and immunologic phenotype. The careful analysis of the pattern of inheritance of PIDs, and the availability of more potent immunologic tools, such as MAb and sophisticated assays to explore the phenotype and function of immune cells, have helped identify an unexpected heterogeneity within clinically homogeneous forms of PID. For example, both X-linked and autosomal recessive forms of SCID have been identified; furthermore, it became clear that-while retaining similar clinical features and the consistent lack of circulating T cells-infants with SCID may or may not present deficiencies also of B and/or NK lymphocytes (2). Similarly, X-linked and autosomal recessive forms of congenital agammaglobulinemia and of CGD were disclosed.The heterogeneity of PIDs was further illustrated when advances in molecular genetics and the development of the Human Genome Project made cloning of PID-causing genes feasible. Yet, many forms of PID are still "orphan" as to the genetic defect...

Impaired TH17 responses in patients with chronic mucocutaneous candidiasis with and without autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy

“…In other primary immune deficiency syndromes, such as severe combined immune deficiency, it is well documented that different genetic mutations affecting distinct immune pathways underlie what appears to be similar pathology. 29,30 In analogy, patients with CMC might have similar clinical problems, even though different immune response pathways important in protection against Candida species might be involved.…”

Human genetic basis of interindividual variability in the course of infection

“…Other spectacular achievements have been made in the domain of therapy, including the first successful cases of hematopoietic stem cell transplantation in 1968 (118) and gene therapy in 2000 (119). Increasingly diverse clinical phenotypes, extending beyond infection and including various autoinflammatory, allergic, and autoimmune phenotypes, have been attributed to primary immunodeficiencies (120)(121)(122)(123)(124). Autoimmune phenotypes include systemic and organ-specific conditions such as the intriguingly related and occasionally allelic systemic lupus erythematosus and neurological Aicardi-Goutières syndrome, two type I interferonopathies (125).…”

The molecular basis of pulmonary alveolar proteinosis

“…The diagnosis is usually made based on the presence of typical radiological manifestations and lung histopathological findings. Secondary PAP has been reported in association with various diverse clinical disorders, including hematological disorders (myelodysplastic syndrome, leukemia, lymphoma, aplastic anemia, pharmacologically induced leukopenia, others), immunological diseases (severe combined immunodeficiency, monoclonal gammopathy, selective immunoglobulin A deficiency, others), lysinuric protein intolerance, and infections (Cytomegalovirus, Mycobacterium tuberculosis , Nocardia, Pneumocystis jiroveci , others) [34; 62; 63; 64; 65; 66; 67; 68; 69; 70; 71; 72; 73; 74; 75; 76; 77; 78; 79; 80]. It has also been reported in association with various toxic inhalation syndromes, including inhalation of inorganic dusts (silica, cement, titanium, and aluminum), organic dusts (sawdust, fertilizer, bakery flour, others), and fumes (chlorine, varnish, others) [81; 82; 83; 84; 85; 86; 87; 88].…”