Molecular defects in T- and B-cell primary immunodeficiency diseases

Abstract

More than 120 inherited primary immunodeficiency diseases have been discovered in the past five decades, and the precise genetic defect in many of these diseases has now been identified. Increasing understanding of these molecular defects has considerably influenced both basic and translational research, and this has extended to many branches of medicine. Recent advances in both diagnosis and therapeutic modalities have allowed these defects to be identified earlier and to be more precisely defined, and they have also resulted in more promising long-term outcomes. The prospect of gene therapy continues to be included in the armamentarium of treatment considerations, because these conditions could be among the first to benefit from gene-therapy trials in humans.

Can we explain the higher prevalence of autoimmune disease in women?

“…They can develop autoimmune events such as hemolytic anemia, inflammatory bowel disease and hypothyroidism, as well as suffer from infections [34]. Other inherited X-linked disorders are the Wiskott�Aldrich syndrome, X-linked agamma globulinemia and X-linked recessive anhidrotic ectodermal dysplasia with immuno deficiency [35][36][37]. These diseases are usually more dramatic in males, while in females the second X chromosome can compensate for the mutant one.…”

Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency

“…Severe combined immunodeficiency (SCID) is a primary immunodeficiency that is characterized by severely reduced numbers or the total absence of functional T-cells, which, in turn, results in the absence of an adaptive immune response, including strongly reduced or virtually absent serum immunoglobulin (Ig) levels [4]. Despite the presence of various underlying genetic defects, patients usually have a common clinical picture with opportunistic infections, leading to failure to thrive.…”

Peptide library-based evaluation of T-cell receptor breadth detects defects in global and regulatory activation in human immunologic diseases

“…The defined length of 15 amino acids optimized the system for stimulation of CD4 cells (23), and similar approaches in CD8 cells would be complicated by strict peptide length requirements (24). Twenty pools (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) were fixed with one of each of the 20 amino acids at position five, another 20 (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) at position six, and another 20 (41-60) at position eight. Each of the nonfixed positions was synthesized with a random amino acid.…”

“…As the specific ligands that will be encountered are unknown, the immune system relies on maintaining a diverse TCR repertoire to ensure effective responses. "Holes," or skewing of the repertoire, lead to missing responses and infection, as seen in HIV (1), aging (2) and various immune deficiencies (3), or abnormal responses leading to autoimmunity or atopy (4).…”