We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases.

/pdf/human-inborn-errors-of-immunity-2019-update-on-the-38qelf7u12.pdf

Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee

Molecular, cellular, and clinical studies of human inborn errors of immunity have revolutionized our understanding of their pathogenesis, considerably broadened their spectrum of immunological and clinical phenotypes, and enabled successful targeted therapeutic interventions. These studies have also been of great scientific merit, challenging a number of immunological notions initially established in inbred mice while revealing previously unrecognized mechanisms of host defense by leukocytes and other cells and of both innate and adaptive tolerance to self.

https://immunology.sciencemag.org/content/immunology/5/49/eabb1662.full-text.pdf

Human inborn errors of immunity: An expanding universe.

Treg cells in health and autoimmune diseases: New insights from single cell analysis.

https://pure.rug.nl/ws/files/147438457/1_s2.0_S2213260020303635_main.pdf

The genetics of asthma and the promise of genomics-guided drug target discovery

Follicular helper T (TFH) cells provide help to B cells, supporting the formation of germinal centres that allow affinity maturation of antibody responses. Although usually located in secondary lymphoid organs, T cells bearing features of TFH cells can also be identified in human blood, and their frequency and phenotype are often altered in people with autoimmune diseases. In this Perspective article, I discuss the increase in circulating TFH cells seen in autoimmune settings and explore potential explanations for this phenomenon. I consider the multistep regulation of TFH cell differentiation by the CTLA4 and IL-2 pathways as well as by regulatory T cells and highlight that these same pathways are crucial for regulating autoimmune diseases. The propensity of infection to serve as a cue for TFH cell differentiation and a potential trigger for autoimmune disease development is also discussed. Overall, I postulate that alterations in pathways that regulate autoimmunity are coupled to alterations in TFH cell homeostasis, suggesting that this population may serve as a core sentinel of dysregulated immunity. Individuals with autoimmunity often have an increased frequency of T cells bearing features of follicular helper T cells in their blood. Lucy Walker proposes that alterations in pathways that regulate autoimmunity are coupled to alterations in follicular helper T cell homeostasis. 

/pdf/the-link-between-circulating-follicular-helper-t-cells-and-77idrpex.pdf

The link between circulating follicular helper T cells and autoimmunity

Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) β chain (IL2RB) gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the IL2RB gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rβ and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rβ expression and function. IL-2Rβ loss of function was recapitulated in a recombinant system in which IL2RB mutations caused reduced surface expression and IL-2 binding. Stem cell transplant ameliorated clinical symptoms in one patient; forced expression of wild-type IL-2Rβ also increased the IL-2 responsiveness of patient T lymphocytes in vitro. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.

/pdf/human-interleukin-2-receptor-b-mutations-associated-with-byp3bcjxp7.pdf

Human interleukin-2 receptor β mutations associated with defects in immunity and peripheral tolerance.

Interleukin-2, which conveys essential signals for effective immunity and immunological tolerance, operates through a heterotrimeric receptor comprised of alpha, beta, and gamma chains. Genetic deficiency of the alpha or gamma chain causes debilitating disease. Here we identify human interleukin-2 receptor (IL-2R) beta chain (CD122) gene defects as a cause of life-threatening dysregulation of immunity and peripheral tolerance. We report homozygous mutations in the human IL-2Rbeta gene from four consanguineous families, comprising either recessive missense mutations in five children or an early stop-gain mutation in two deceased fetuses and a premature neonate. All patients surviving to childhood presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, and dermatological abnormalities, as well as cytomegalovirus disease in most cases. Patient T lymphocytes lacked surface expression of IL-2Rbeta and were unable to normally respond to high-dose IL-2 stimulation. By contrast, patient natural killer (NK) cells retained partial IL-2Rbeta expression and cytotoxic function. IL-2Rbeta loss of function was recapitulated in a recombinant system, in which endoplasmic reticulum sequestration was revealed as the mechanism by which certain missense mutations cause disease. Hematopoietic stem cell transplant resulted in resolution of clinical symptoms in one patient. The hypomorphic nature of this disease highlights the significance of variable IL-2Rbeta expression in different lymphocyte subsets as a means of modulating immune function. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.

https://www.biorxiv.org/content/biorxiv/early/2018/11/26/476697.full.pdf

Human IL-2 receptor β mutations associated with defects in immunity and peripheral tolerance

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Human interleukin-2 receptor β mutations associated with defects in immunity and peripheral tolerance.

Human IL-2 receptor β mutations associated with defects in immunity and peripheral tolerance