A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency

IRF4 International Consortium

Science Immunology, 2018; 19 (9): 973-985.

Interferon regulatory factor 4 (IRF4) is a transcription factor (TF) and key regulator of immune cell development and function. We report a recurrent heterozygous mutation in IRF4, p.T95R, causing an autosomal dominant combined immunodeficiency (CID) in seven patients from six unrelated families. The patients exhibited profound susceptibility to opportunistic infections, notably Pneumocystis jirovecii, and presented with agammaglobulinemia. Patients' B cells showed impaired maturation, decreased immunoglobulin isotype switching, and defective plasma cell differentiation, whereas their T cells contained reduced T_H17 and TF_H populations and exhibited decreased cytokine production. A knock-in mouse model of heterozygous T95R showed a severe defect in antibody production both at the steady state and after immunization with different types of antigens, consistent with the CID observed in these patients. The IRF4^T95R variant maps to the TF's DNA binding domain, alters its canonical DNA binding specificities, and results in a simultaneous multimorphic combination of loss, gain, and new functions for IRF4. IRF4^T95R behaved as a gain-of-function hypermorph by binding to DNA with higher affinity than IRF4^WT. Despite this increased affinity for DNA, the transcriptional activity on IRF4 canonical genes was reduced, showcasing a hypomorphic activity of IRF4^T95R. Simultaneously, IRF4^T95R functions as a neomorph by binding to noncanonical DNA sites to alter the gene expression profile, including the transcription of genes exclusively induced by IRF4^4T95R but not by IRF4^WT. This previously undescribed multimorphic IRF4 pathophysiology disrupts normal lymphocyte biology, causing human disease.

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Clinical and Immunological Features of Human BCL10 Deficiency

Garcia Solis B^#, Van Den Rym A^#, Pérez-Caraballo JJ^#, Al –Ayoubi A, Alazami AM, Lorenzo L, Cubillos-Zapata C, López-Collazo E, Perez-Martinez A, Allende LM, Markle J, Fernandez-Arquero M, Sánchez-Ramón S, Recio MJ, Casanova JL, Mohammed R, Martinez-Barricarte R*, Pérez de Diego R*

Frontiers in Immunology, 2021

The CARD-BCL10-MALT1 (CBM) complex is critical for the proper assembly of human immune responses. The clinical and immunological consequences of deficiencies in some of its components such as CARD9, CARD11, and MALT1 have been elucidated in detail. However, the scarcity of BCL10 deficient patients has prevented gaining detailed knowledge about this genetic disease. Only two patients with BCL10 deficiency have been reported to date. Here we provide an in-depth description of an additional patient with autosomal recessive complete BCL10 deficiency caused by a nonsense mutation that leads to a loss of expression (K63X). Using mass cytometry coupled with unsupervised clustering and machine learning computational methods, we obtained a thorough characterization of the consequences of BCL10 deficiency in different populations of leukocytes. We showed that in addition to the near absence of memory B and T cells previously reported, this patient displays a reduction in NK, γδT, Tregs, and TFH cells. The patient had recurrent respiratory infections since early childhood, and showed a family history of lethal severe infectious diseases. Fortunately, hematopoietic stem-cell transplantation (HSCT) cured her. Overall, this report highlights the importance of early genetic diagnosis for the management of BCL10 deficient patients and HSCT as the recommended treatment to cure this disease.

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Isolated Nocardiosis, an Unrecognized Primary Immunodeficiency?

Martínez-Barricarte R*

Frontiers in Immunology, 2020

Nocardiosis is an infectious disease caused by the gram-positive bacterium Nocardia spp. Although it is commonly accepted that exposure to Nocardia is almost universal, only a small fraction of exposed individuals develop the disease, while the vast majority remain healthy. Nocardiosis has been described as an “opportunistic” disease of immunocompromised patients, suggesting that exposure to the pathogen is necessary, but a host predisposition is also required. Interestingly, increasing numbers of nocardiosis cases in individuals without any detected risk factors, i.e., without overt immunodeficiency, are being reported. Furthermore, a growing body of evidence have shown that selective susceptibility to a specific pathogen can be caused by a primary immunodeficiency (PID). This raises the question of whether an undiagnosed PID may cause nocardiosis affecting otherwise healthy individuals. This review summarizes the specific clinical and microbiological characteristics of patients with isolated nocardiosis published during the past 30 years. Furthermore, it gives an overview of the known human immune mechanisms to fend off Nocardia spp. obtained from the study of PIDs and patients under immunomodulatory therapies.

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Both IL-12 and IL-23 govern human IFN-γ immunity to mycobacteria

Martínez-Barricarte R*, Markle J*, Ramirez-Alejo N, Ma CS, Deenick EK, Mele F, Latorre D, Jovic S, Aytekin C, Mahdaviani SA, Kong XF, Jabot-Hanin F, Deswarte C, Kerner G, Itan Y, Bigio B, Boisson B, Ikinciogullari A, Dogu F, Tanir G, Joseph JK, Heer A, Migaud M, Emile JF, van de Vosse E, Schmidt M, Müller Fleckenstein I, Fleckenstein B, Sette A, Puel A, Mansouri D, Abel L, Boisson-Dupuis S, Bustamante J, Sallusto F, Tangye SG, Casanova JL.

Science Immunology, 2018; 3(30). pii: eaau6759

Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rβ1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL-12–dependent IFN-γ immunity and IL-23–dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL-12Rβ2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that ab T, γδ T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-γ in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-γ in response to IL-23. We also show that the development of IFN-γ–producing CD4⁺ T cells, including, in particular, mycobacterium-specific TH1* cells (CD45RA^-CCR6⁺), is dependent on both IL-12 and IL-23. Last, we show that IL12RB1, IL12RB2, and IL23R have similar frequencies of deleterious variants in the general population. The comparative rarity of symptomatic patients with IL-12Rβ2 or IL-23R deficiency, relative to IL-12Rb1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R– and IL-12Rβ2–deficient than IL-12Rβ1–deficient patients, not because these genetic disorders are rarer, but because the isolated absence of IL-12 or IL-23 is, in part, compensated by the other cytokine for the production of IFN-γ, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-γ–dependent immunity to mycobacteria, both individually and much more so cooperatively.

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