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Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23–dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.

The rst molecular evidence of a monogenic predisposition to mycobacteria came from the study of Mendelian susceptibility to mycobacterial disease (MSMD). We aimed to study this Mendelian susceptibility to mycobacterial diseases in Moroccan kindreds through clinical, immunological and genetic analysis. MethodsPatients presented with clinical features of MSMD, were recruited into this study. We used whole blood samples from patients and age-matched healthy controls. To measure IL-12 and IFN-γ production, samples were activated by BCG plus recombinant human IFN-γ or recombinant human IL-12. Immunological assessments and genetic analysis were also done for patients and their relatives. ResultsOur study involved 22 cases from 15 unrelated Moroccan kindreds. The average age at diagnosis is 4 years. Fourteen patients (64%) were born to consanguineous parents. All patients were vaccinated with BCG vaccine, twelve of them (55%) developed loco-regional or disseminated BCG infections. The other symptomatic patients had severe tuberculosis and/or recurrent salmonellosis. Genetic mutations were identi ed on the following genes: IL12RB1 in 8 patients, STAT1 in 7 patients, SPPL2A, IFNGR1 and TYK2 in two patients and TBX21 in one patient, with different modes of inheritance. All identi ed mutations/variants altered production or response to IFN-γ or both. ConclusionSevere forms of tuberculosis and complications of BCG vaccination may imply a genetic predisposition present in the Moroccan population. In front of these infections, systematic genetic studies became necessary. BCG vaccination is contraindicated in MSMD patients and should be delayed in newborns siblings until the exclusion of a genetic predisposition to mycobacteria.

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.

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Objective Systemic sclerosis (SSc) is a connective tissue disorder characterized by excessive fibrosis of the skin and internal organs, along with microvascular damage, and is often associated with typical autoantibodies. This study aimed to analyze the correlation between specific autoantibody profiles, clinical and paraclinical features in Moroccan patients with SSc. Methods We analyzed the presence of specific autoantibodies in 46 SSc patients using indirect immunofluorescence (IIF) on Hep-2 cells and immunodot. We then correlated the type of autoantibodies with clinical and laboratory manifestations. Results Among our patients, 86.9% were females. The mean age of patients at diagnosis was 50.21 years old, with an average diagnosis delay of 5 years. The main clinical manifestations found were Raynaud’s phenomenon (89.2%), sclerodactyly (84.8%), proximal scleroderma (67.4%), gastrointestinal involvement (50%), and interstitial lung disease (30.4%). According to the specific autoantibody profile, 14 patients were anti-topo I positive (30.4%), 8 were anti-RNP(68kDa/A/C) positive (17.4%) and 6 were anti-RNA polymerase III positive (13%). We found a significant association of Anti-RNAP III with sclerodactyly and pulmonary arterial hypertension (p < 0.05). We also found an association between anti-topo I and interstitial lung disease in 30.4% of patients. There was no significant association between the positivity for the autoantibodies and other diagnosed clinical manifestations. Conclusion Some clinical manifestations of SSc may correlate positively with the presence of specific autoantibodies. Environmental factors, ethnicity, and gene interaction may also influence this correlation. Lay summary What does this mean for patients? Systemic sclerosis (SSc) is a disease that affects the connective tissues, causing excessive skin and internal organs fibrosis and microvascular damage. Specific autoantibodies, which are antibodies that attack the body's tissues, are responsible for amplifying the immune response and targeting cells involved in the development of SSc. This study aimed to investigate the relationship between specific autoantibodies and the clinical and laboratory features of SSc in 46 Moroccan patients. The majority of patients were female, middle-aged, and of Caucasian ethnicity, with a mean age of 50 years, and duration of disease between 1 and 10 years. The most common symptoms were Raynaud’s phenomenon (89.2% of patients), sclerodactyly (84.8%), proximal scleroderma (67.4%), gastrointestinal involvement (50%), arthralgia (41.3%), interstitial lung disease (30.4%), myalgia (24%) and pulmonary arterial hypertension (10.8%). We found a correlation between anti-RNAP III and Sclerodactyly and pulmonary arterial hypertension, while anti-topo I autoantibodies were associated with interstitial lung disease. The study also noted that environmental factors, ethnicity, and genetic interactions may influence the clinical and autoantibody profile in SSc patients.