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Systemic lupus erythematosus (SLE) presents a complex clinical landscape with diverse manifestations, suggesting a multifactorial etiology. However, the identification of rare monogenic forms of the disease has shed light on specific genetic defects underlying SLE pathogenesis, offering valuable insights into its underlying mechanisms and clinical heterogeneity. By categorizing these monogenic forms based on the implicated signaling pathways, such as apoptotic body clearance, type I interferon signaling, JAK-STAT pathway dysregulation, innate immune receptor dysfunction and lymphocytic abnormalities, a more nuanced understanding of SLE's molecular basis emerges. Particularly in pediatric populations, where monogenic forms are more prevalent, routine genetic testing becomes increasingly important, with a diagnostic yield of approximately 10% depending on the demographic and methodological factors involved. This approach not only enhances diagnostic accuracy but also informs personalized treatment strategies tailored to the specific molecular defects driving the disease phenotype.

Title: Maladies auto-immunes rares : place de la génétique, exemple du lupus systémique. Abstract: Le lupus érythémateux systémique (LES) est une maladie auto-immune chronique caractérisée par une grande hétérogénéité clinique. Certaines formes rares de LES sont causées par des mutations génétiques spécifiques, contrairement à la nature multifactorielle généralement associée à la maladie. Ces formes monogéniques ont été décrites particulièrement dans les cas de LES à début pédiatrique. Leur découverte a permis une meilleure compréhension de la physiopathologie du LES, mettant en lumière la grande complexité des présentations cliniques. Nous proposons ici une classification basée sur les voies de signalisation sous-jacentes, impliquant la clairance des corps apoptotiques et des complexes immuns, les interférons de type I, les voies JAK-STAT, les récepteurs de l'immunité innée et les fonctions lymphocytaires. Dans les formes pédiatriques, un test génétique devrait être proposé systématiquement avec un rendement diagnostique autour de 10 % selon la population et les approches utilisées.

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INTRODUCTION: To assess frequency and methods of PID (primary immune deficiency) screening among patients with bronchiectasis by pneumologists in clinical practice. METHODS: All the patients hospitalized in the department of pneumology of the Poitiers University Hospital between April 2013 and April 2020 with a diagnosis of bronchiectasis on chest computerized tomography were included. Patients aged 70 and over and those with already known PID were excluded. Primary endpoint was the proportion of patients having had serum immunoglobulin (Ig) assay and serum protein electrophoresis (SPE) analysis. Secondary endpoints were factors associated with prescription of SPE and/or Ig assay, proportion of patients with newly diagnosed PID and their characteristics and factors associated with repeated courses of antibiotics. RESULTS: Among the 133 patients included, 43% had SPE+Ig assay, 34% SPE only and 23% neither. The proportion of patients with asthma was higher in the "SPE+Ig assay" group (33.3%) compared to the "SPE only" (11.1%) and the "Neither SPE nor Ig assay" groups (6.4%) (P=0.002). Four patients were newly diagnosed for PID of whom 3 had subclass IgG deficiency. Factors associated with repeated courses of antibiotics were generalized bronchiectasis (P=0.02) and asthma (P=0.04). CONCLUSION: PID is underscreened by pneumologists among patients with bronchiectasis. Association of SPE+Ig assay+IgG subclass assay appears as the most accurate combination.

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Chronic Granulomatosis Disease (CGD) is an inherited immune deficiency due to a mutation in the genes coding for the subunits of the NADPH oxidase enzyme that affects the oxidative capacity of phagocytic cells. It is characterized by increased susceptibility to bacterial and fungal infections, particularly Aspergillus, as well as complications associated with hyperinflammation and granulomatous tissue infiltration. There exist two types of frequently encountered pulmonary manifestations: (1) due to their being initially pauci-symptomatic, possibly life-threatening infectious complications are often discovered at a late stage. Though their incidence has decreased through systematic anti-bacterial and anti-fungal prophylaxis, they remain a major cause of morbidity and mortality; (2) inflammatory complications consist in persistent granulomatous mass or interstitial pneumoniae, eventually requiring immunosuppressive treatment. Pulmonary complications recurring since infancy generate parenchymal and bronchial sequelae that impact functional prognosis. Hematopoietic stem cell allograft is a curative treatment; it is arguably life-sustaining and may limit the morbidity of the disease. As a result of improved pediatric management, life expectancy has increased dramatically. That said, new challenges have appeared with regard to adults: difficulties of compliance, increased inflammatory manifestations, acquired resistance to anti-infectious therapies. These different developments underscore the importance of the transition period and the need for multidisciplinary management.

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Auto-inflammatory diseases (AIDs) are diseases resulting from an inappropriate activation of innate immunity in the absence of any infection. The field of monogenic AIDs is constantly expanding, with the discovery of new pathologies and pathophysiological mechanisms thanks to pangenomic sequencing. Actinopathies with auto-inflammatory manifestations are a new emerging group of AIDs, linked to defects in the regulation of the actin cytoskeleton dynamics. These diseases most often begin in the neonatal period and combine to varying degrees a more or less severe primary immune deficiency, cytopenias (especially thrombocytopenia), auto-inflammatory manifestations (especially cutaneous and digestive), atopic and auto-immune manifestations. The diagnosis is to be evoked essentially in front of a cutaneous-digestive auto-inflammation picture of early onset, associated with a primary immune deficiency and thrombocytopenia or a tendency to bleed. Some of these diseases have specificities, including a risk of macrophagic activation syndrome or a tendency to atopy or lymphoproliferation. We propose here a review of the literature on these new diseases, with a proposal for a practical approach according to the main associated biological abnormalities and some clinical particularities. However, the diagnosis remains genetic, and several differential diagnoses must be considered. The pathophysiology of these diseases is not yet fully elucidated, and studies are needed to better clarify the inherent mechanisms that can guide the choice of therapies. In most cases, the severity of the picture indicates allogeneic marrow transplantation.

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The gastrointestinal tract is the site of exciting immunological interactions between the epithelium and the mucosa-associated lymphoid tissue, leading to the immune response to food and microbial antigens in the digestive lumen. The objective of this review is to present the main dysimmune pathologies of the digestive tract leading to an enteropathy. As examples, we describe celiac and non-celiac enteropathies to clarify a florid diagnostic framework, by identifying a spectrum of elementary lesions, which must be confronted with the clinico biological context of the patient to orient the diagnosis. The microscopic lesions observed are most often non-specific and may be encountered in several diagnostic settings. Moreover, it is a set of elementary lesions in each clinical context that will orient the diagnostic framework. Celiac disease is the main etiology of enteropathy with villous atrophy, its diagnosis is multidisciplinary and there are many differential diagnoses. We will discuss celiac disease lymphomatous complications as enteropathy associated T-cell lymphoma including refractory sprue type 2. We will then present the non-celiac enteropathies. Among these, enteropathies of unknown etiology may be associated with a primary immune deficiency that may be reflected by florid lymphoid hyperplasia of the gastrointestinal tract and/or be associated with an infectious etiology that should also be constantly sought. Finally, we will discuss of induced enteropathy by new immunomodulatory treatments.

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Hypogammaglobulinemia (hypoγ) is defined as a serum IgG level < 7 g/L. It is most often detected on serum protein electrophoresis. Given the existence of transient hypoγ, its persistence should be checked at distance, preferably by requesting a blood test for IgG, IgA and IgM, which will be needed to characterize a possible primary immune deficiency (PID). In the case of association with a monoclonal component, the first step is to look for a cryoglobulin causing a false hypoγ. Otherwise, the etiological investigation is dictated by the clinical examination. For example, the notion of chronic diarrhea should lead to a search for an enteropathy causing a digestive loss of gammaglobulins (an ambiguous situation because some DIP can be complicated by an enteropathy). In the absence of an obvious explanation, a secondary cause must first be ruled out (secondary immune deficiencies are 30 times more common than PID). The first simple test to perform is 24-hour proteinuria, coupled with urinary protein electrophoresis, to rule out 2 diagnoses: nephrotic syndrome and light chain myeloma. Subsequently, blood immunophenotyping looking for a circulating B clone is recommended, allowing the investigations to be directed towards a lymphoid hemopathy. Drug-induced hypoγ may also be suspected if certain drugs such as corticosteroids, anti-epileptics or immunosuppressive agents (especially anti-CD20) are taken. The profile of a drug-induced hypoγ is different from that of a DIP: it is rarely profound, the IgA level is preserved and there is no deficit in switched memory B lymphocytes. Finally, a thoracoabdominal CT-scan will help to rule out a thymoma and identify a deep tumor syndrome. If all these tests are normal, a PID is suspected, the leader of which in adults remains the common variable immunodeficiency, which is the most frequent symptomatic PID in adults.

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INTRODUCTION: Heterozygous germline mutations of GATA2 gene (guanine-adenine-thymine-adenine binding protein 2) are hereditary mutations that can be pathogenic, sometimes occurring sporadically, responsible for a florid clinical-biological picture, sometimes serious and quickly leading to the death. CASE REPORTS: We reported two women and one man with germline mutations in the GATA2 gene. The first patient, aged 19, initially presented with monocytopenia and chronic lymphedema of the four limbs, suggestive of Emberger syndrome. The second patient, 28-years-old, presented with a disseminated atypical mycobacterium (Mycobacterium kansasii) infection, raising suspicion of an immune deficiency such as MonoMAC syndrome (deficiency syndrome of dendritic cells, monocytes, B lymphocytes and NK cells). The last patient, 30-years-old, presented with pancytopenia, leading to the diagnosis of a family form of myelodysplastic syndromes and acute myeloid leukemia characterized by a mutation of the GATA2 gene. CONCLUSIONS: Each case illustrates a typical clinical presentation of GATA2 deficiency, although the evolution of these syndromes ultimately reveals a complex, heterogeneous and intricate picture of hematological, dermatological, infectious, pulmonary, ENT or oncological symptoms. Mutations in the GATA2 gene remain a diagnostic and therapeutic challenge for the internist, and require multidisciplinary management given the florid picture that can be of interest to all specialties. The clinical spectrum of these GATA2 mutations as well as the latest management recommendations from the recent litterature and the "GATA2 club" are described in this article.

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Anti-cytokine antibodies (ACA) are an emerging cause of acquired immunodeficiency, especially in previously healthy adults. The most frequently reported are anti-IFN-γ responsible for disseminated non-tuberculous mycobacteria infections, and anti-GM-CSF mainly in mycobacteria, cryptococcosis and nocardiosis infections. The presence of anti-IFN-α in severe COVID-19 infections has recently been described. The search for and detection of these ACAs in an unusual infection situation makes it possible to set up specific therapies in addition to the anti-infective treatment. ACAs are also frequent in various autoimmune pathologies where, in addition to being indicators of the breakdown of immune tolerance, they can modulate the activity of the disease according to their cytokine target. In this review of the literature, we will focus on the epidemiology and the clinical impact of these ACAs in healthy subjects and in infectious or dysimmune diseases.

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Autoinflammatory diseases related to RIPK1 mutations have been recently described. Two distinct clinical phenotypes have been reported and depend on the type and location of the mutation. When the mutation is recessive with loss of function, patients develop a combined phenotype of immune deficiency with recurrent bacterial and fungal infections and signs of early inflammatory bowel disease, non-erosive polyarthritis and growth retardation. On the other hand, when the mutation is dominant, gain of function, the manifestations are only auto-inflammatory with extensive lymphoproliferation, oral lesions such as aphthosis or ulcers, abdominal pain and hepatosplenomegaly. The mutations described for the dominant form affect only the cleavage site of caspase 8 and the clinical phenotype is called CRIA for Cleavage-Resistant RIPK1-Induced Autoinflammatory syndrome. The recessive form is severe and life-threatening requiring hematopoietic stem cell transplantation while the dominant form responds well to interleukin-6 receptor antagonists. Thus, RIPK1 mutations can induce various clinical manifestations with two distinct phenotypes. Although still rare, because of their recent description, these diseases can be suspected by an internist, in front of recurrent digestive features and will be increasingly diagnosed in the future through the integration of this gene in the diagnostic chips dedicated to autoinflammatory diseases and early inflammatory bowel diseases, using next generation sequencing.

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Mucocutaneous fungal infections are common and usually occur in the presence of certain risk factors. However, these infections can occur in patients with no known risk factors. This indicates the presence of an underlying genetic susceptibility to fungi reflecting an innate or adaptive immune deficiency. In this review, we highlight genetic factors that predispose to mucocutaneous fungal infections specially candidiasis and dermatophytosis.

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Common variable immunodeficiency disorders (CVID) are a heterogeneous group of conditions with hypogammaglobulinemia as the common denominator. These are the most common symptomatic primary immunodeficiency disorder in adults. Two different clinical forms are described: one group only develops infections, while a second includes (sometimes without infections, at least at the onset of disease course) a variety of non-infectious autoimmune, inflammatory, granulomatous and/or lymphoproliferative manifestations, sometimes revealing the disease and often observed in Internal Medicine. The international diagnostic criteria for CVID were updated in 2016 and are the subject of several comments in this general review. The recent use of new sequencing techniques makes it possible to better genetically define CVID. The identification of such a genetic disease makes it possible to treat pathophysiologically, in particular autoimmune and lymphoproliferative complications, with targeted treatments, sometimes used in other diseases. Determining a genetic disease in these patients also makes it possible to provide appropriate genetic counseling, and therefore to monitor mutated individuals, symptomatic or not.

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Common variable immunodeficiency disorders (CVID) are the most common symptomatic primary antibody deficiency in adults with an estimated prevalence of 1/25,000. The most frequent clinical manifestations are upper respiratory tract infections (including pneumonia, bronchitis, and sinusitis) predominantly with Streptococcus pneumoniae or H. influenzae. However, CVID are complicated in 20 to 30 % of cases of non-infectious manifestations which have been well characterized in recent years. Several complications can be observed including autoimmune, lymphoproliferative, granulomatous or cancerous manifestations involving one or more organs. These complications, mostly antibody-mediated cytopenias, are correlated with a decrease in the number of circulating switched memory B cells. Replacement therapy with polyvalent gammaglobulins has greatly improved the prognosis of these patients but it remains poor in the presence of digestive complications (especially in the case of chronic enteropathy and/or porto-sinusoidal vascular disease), pulmonary complications (bronchiectasis and/or granulomatous lymphocytic interstitial lung disease) and when progression to lymphoma. Much progress is still to be made, in particular on the therapeutic management of non-infectious complications which should benefit in the future from targeted treatments based on knowledge of genetics and immunology.

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Secondary forms of immune thrombocytopenia (ITP) represent approximately 20% of all ITP cases in adulthood and this rate increases with age. Since some causes may influence both the prognosis and outcome but also the management of ITP, a minimal workup must be performed at ITP diagnosis to look for an associated or underlying cause. Among adults, B-cell lymphomas and mainly chronic lymphocytic leukemia, systemic auto-immune diseases such as systemic lupus or primary immunodeficiencies mainly represented by common variable immunodeficiency are the most frequent causes of secondary ITP. Whereas first-line therapy used for secondary ITP is usually similar to the one commonly used in primary ITP and relies mostly on corticosteroids±intravenous immunoglobulin according to the severity of bleeding, second and third-line treatments must take into account the type and degree of activity of the underlying disease.

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OBJECTIVES: Securing the supply of immunoglobulins is essential in indications without therapeutic alternatives, such as primary immunodeficiencies (PIDs). The objective was to obtain an inventory of patients with PID, and to quantify their immunoglobulin needs. METHODS: The retrospective study was conducted using data from January to June 2018, in Bordeaux, Lyon and Paris (Saint-Louis). Patients with PID were included based on the pharmaceutical traceability of the 3 centres. The concordance between the patients included and the patients in the CEREDIH register was analysed. RESULTS: For the 361 patients included (sex ratio: M/F 0.8; mean age: 45±20years, mean weight: 62±19kg), 2082 dispensations were performed for a total volume of 57kg of immunoglobulins. Of the 108 specialty changes identified, 68% were due to supply tensions. In total, the analysis of CEREDIH data made it possible to identify 727 patients with PID and followed up once in the study centres, 161 of whom were recorded in the 2 data follow-ups (patients included and CEREDIH). CONCLUSIONS: A complete overview of immunoglobulin needs in PIDs is difficult to obtain. Supply tensions have been observed although PIDs are a priority indication. Measures must be proposed to ensure an adequate supply regardless of the location of patients in the territory.

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BACKGROUND: Severe combined immunodeficiency (SCID) is a the most severe form of primary immunodeficiency and is highly heterogeneous. We report an atypical form of SCID revealed by exfoliative erythroderma. PATIENTS AND METHODS: A 3-month-old boy, born to consanguineous parents, was admitted to the dermatology department with exfoliative erythroderma associated with eczematous patches and alopecia of the scalp, eyelashes, and eyebrows, but with no lymphadenopathy or hepatosplenomegaly. He displayed chronic diarrhea and recurrent infection since birth. A complete blood count showed marked leukocytosis with eosinophilia and lymphocytosis. These clinical and biological findings improved partly with topical steroids. The patient no longer had erythroderma and showed regrowth of hair, eyelashes and eyebrows. The subsequent CBC showed less marked eosinophilia with mild lymphopenia and no leukocytosis. Immunoglobulin levels were undetectable. Primary immunodeficiency was discussed. Immunological investigations concluded on a diagnosis of T-B-NK+ SCID. Mutation analysis revealed a homozygous c.1338C>G (pCys446Trp) mutation in the RAG2 gene. Hematopoietic stem cell transplantation is planned in the near future. CONCLUSION: This case illustrates atypical T-B-NK+ SCID revealed by severe exfoliative erythroderma in a 3-month-old boy with RAG2 gene mutation. Neonatal erythroderma must be considered a warning sign of primary immunodeficiency requiring immediate immunological phenotyping as well as genetic testing for a definitive diagnosis.

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INTRODUCTION: Chronic mucocutaneous candidiasis (CMC) is characterized by susceptibility to chronic or recurrent infections with yeasts of the genus Candida affecting the skin, nails and mucous membranes. We describe a Moroccan patient presenting CMC with heterozygous STAT1 gain-of-function (GOF) mutation. PATIENTS AND METHODS: A 5-year-old boy with no consanguinity presented recurrent episodes of oral thrush, chronic nail candidiasis and herpetic gingivostomatitis from the age of 8 months. He also had mycobacterial adenitis secondary to BCG vaccination and atypical rosacea. Genetic analysis revealed GOF mutation of the STAT1 gene. DISCUSSION: CMC was diagnosed in our patient despite poor clinical features. Sequencing of the genome revealed STAT1GOF mutation. This mutation affects production of IL-17, an important cytokine in mucocutaneous defense against Candida. The association with mycobacterial adenitis is rare and continues to be poorly understood. The presence of atypical rosacea in this setting is suggestive of this entity. Antifungal therapy and prevention of complications are necessary to reduce the morbidity and mortality associated with this condition. CONCLUSION: CMC due to STAT1GOF mutation is characterized by a broad clinical spectrum and should be considered in all cases of chronic or recurrent fungal infection, whether or not associated with other infections.

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After intensive chemotherapy followed by an allograft of haematopoietic stem cells, patients are immunocompromised for several months, or even years. They are vulnerable to bacteria and viral and fungal infections, and they must be made aware of the strict hygiene precautions to follow before they return home. Working alongside these patients in a therapeutic education approach, the nurse informs and guides them on the practices to adopt and the warning signs to look out for in the event of complications.

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BACKGROUND: Primary immunodeficiencies are rare and frequently life-threatening conditions in the first year of life. They may present with isolated skin manifestations and the absence of other clinical signs may delay diagnosis and management of the disease. Herein we describe a case of IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome) that illustrates this situation. PATIENTS AND METHODS: A 2.5-month-old boy was seen with a psoriasiform eruption. Despite applications of topical steroids, skin lesions progressed to severe exfoliative ichtyosiform erythroderma. A skin biopsy showed keratinocyte necrosis with a dense, epidermotropic, lymphocytic CD8+ infiltrate. The infant presented increased serum IgE and eosinophilia. He developed an enteropathy with severe and profuse diarrhea, septicemia and hypovolemic shock that led to sudden cardiac arrest. DNA analysis revealed a mutation in the FOXP3 gene, confirming IPEX syndrome. A favorable outcome was achieved following allogeneic bone marrow transplant. DISCUSSION: IPEX syndrome is characterized by early secretory enteropathy with profuse diarrhea, dermatitis and diabetes mellitus. Onset usually occurs within the first weeks or months of life, and the natural course of the disease is often lethal. Cutaneous manifestations appear to be mostly eczematiform, psoriasiform or ichthyosiform. These may be the first sign of the disease and a common inflammatory skin disorder may be wrongly diagnosed. The severity of the lesions and their limited response to topical steroids should alert the clinician. CONCLUSION: The early onset of severe cutaneous manifestations with persistent lesions and poor response to topical steroids should lead to an early skin biopsy. If histopathological changes show a cytotoxic lymphocytic infiltrate with keratinocyte necrosis, a diagnosis of primary immunodeficiency must be considered enabling rapid intitation of specific management.

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INTRODUCTION: Ten to 15% of common variable immunodeficiencies (CVID) develop auto-immune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP). Treatment is based on immunosuppressants, which produce blocking effects in the CVID. Our objective was to assess their risk-benefit ratio in these immunocompromised patients. METHODS: We identified 17 articles detailing the treatment of AIHA and/or ITP in patients suffering from CVID through a systematic review of the MEDLINE database. RESULTS: The increased infectious risk with corticosteroids does not call into question their place in the first line of treatment of ITP and AIHA in CVID. High-doses immunoglobulin therapy remain reserved for ITP with a high risk of bleeding. In second-line treatment, rituximab appears to be effective, with a lower infectious risk than the splenectomy. Immunosuppressants (azathioprine, methotrexate, mycophenolate, cyclophosphamide, vincristine, ciclosporine) are moderately effective and often lead to severe infections, meaning that their use is justified only in resistant cases and steroid-sparing. Dapsone, danazol and anti-D immunoglobulins have an unfavorable risk-benefit ratio. The place of TPO receptor agonists is still to be defined. The establishment of immunoglobulin replacement in the place of immunosuppressants (except for short-term corticotherapy) or splenectomy appears to be essential to limit the risk of infections, including in the absence of previous infections. CONCLUSION: The presence of CVID does not mean that it is necessary to give up on corticosteroids as a first-line treatment and rituximab as a second-line treatment for AIHA and ITP, but it should be in addition to immunoglobulin replacement. A splenectomy should be reserved as a third-line treatment.

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Immunoglobulin preparations are medicines derived from blood used as a replacement therapy for immunodeficiencies or as an immunomodulator. While they are generally well-tolerated, side effects, rarely severe, can nevertheless occur when administered intravenously. They are usually related to an excessive perfusion rate. The recent arrival of safer products administered subcutaneously represents progress in the treatment of patients.

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