Visceral leishmaniasis (VL) is a neglected vector-borne disease caused by obligate intracellular protozoa of the genus Leishmania. In immunocompromised patients, VL may present atypically, progress more aggressively, and respond less favorably to treatment. We present the case of a 62-year-old male with chronic inflammatory demyelinating polyneuropathy (CIDP) receiving long-term corticosteroids and azathioprine who developed relapsing VL complicated by post-kala-azar dermal leishmaniasis (PKDL). The patient initially presented with prolonged fever, pancytopenia, hepatosplenomegaly, and weight loss. Bone marrow aspirate revealed Leishmania amastigotes. Intravenous lyposomal amphotericin B (L-AMB) achieved temporary remission; however, PKDL and VL recurred one year later. Despite receiving sequential therapy with L-AMB and miltefosine, the patient experienced further relapses, likely due to severe T- and B-cell lymphopenia and marasmic-like malnutrition. VL should be considered in the differential diagnosis of prolonged fever and cytopenias in immunosuppressed patients in Mediterranean Europe, even in the absence of travel history. Chronic immunosuppression, secondary immunodeficiency, and malnutrition can significantly impair treatment response and favor recurrence, highlighting the need for integrated clinical, nutritional, and epidemiological management strategies.

Severe combined immunodeficiency (SCID) is a congenital immunodeficiency characterized by significant numerical or functional defects in T lymphocytes and is often accompanied by B lymphocyte dysfunction. It presents early in life with severe, recurrent opportunistic infections. Early diagnosis and hematopoietic stem cell transplantation (HSCT) are vital for patient survival. Cernunnos/XLF deficiency is an autosomal recessive form of SCID caused by mutations in the NHEJ1 gene, which plays a critical role in repairing DNA double-strand breaks. First described in 2006, this condition remains exceedingly rare, with only about 55 cases reported to date. This study aimed to describe a novel infant with Cernunnos/XLF deficiency and to review previously reported patients carrying the same variant, thereby expanding the clinical spectrum of this rare disease. With written informed consent, we retrospectively evaluated a pediatric patient with Cernunnos/XLF deficiency followed at our clinic. Demographic, clinical, laboratory, and radiological findings were reviewed. The diagnosis was based on clinical and immunological features and confirmed via clinical exome sequencing. A literature review was conducted to compare the genotype-phenotype correlations of previously reported patients carrying the same NHEJ1 variant. We report an infant who was hospitalized at 6.5months of age with a preliminary diagnosis of meningitis and was subsequently diagnosed with Cernunnos/XLF deficiency. The patient exhibited microcephaly, growth retardation, recurrent infections, prolonged SARS-CoV-2 PCR positivity, and localized BCGitis following live Bacillus Calmette-Guérin (BCG) vaccination. Immunological evaluation revealed T- and B-cell lymphopenia and hypogammaglobulinemia. Genetic testing confirmed a homozygous nonsense mutation in NHEJ1. HSCT from a matched sibling donor was performed. This study describes a rare case of Cernunnos/XLF deficiency diagnosed in early infancy, underscoring the value of early recognition and the critical role of genetic testing and HSCT. It also expands the clinical spectrum of the disease and provides a comparative perspective with previously reported patients carrying the same mutation. In infants presenting with unexplained infections or complications related to live vaccines, inborn errors of immunity should be considered. Our findings emphasize the importance of timely diagnosis and comprehensive, multidisciplinary follow-up, particularly in patients with additional complications.

Human immunodeficiency virus (HIV)-negative acquired adult immunodeficiency diseases are rare and relatively difficult to diagnose and treat. Good's syndrome is one such rare immunodeficiency syndrome occurring in middle to late adulthood. It is an association of combined B-cell and T-cell immunodeficiency along with hypogammaglobulinemia with a background of thymoma. Here, we describe a case of a 57-year-old male who presented to us with recurrent streptococcal pneumonia. He had a past history of an operated thymoma, cytomegalovirus retinitis, and pure red cell aplasia (PRCA). Evaluation revealed hypogammaglobulinemia along with CD4+ T-cell and B-cell lymphopenia, thus indicating Good's syndrome. Our case highlights the importance of including Good's syndrome in the differential diagnosis of HIV-negative, acquired, adult immunodeficiency and elucidates the general principles of management of this rare clinical entity.

BackgroundLong COVID manifests with heterogeneous clinical outcomes, potentially linked to immune dysfunction. However, the recovery of immune-cell subsets during convalescence remains incompletely understood.MethodsIn this longitudinal cohort, 279 unvaccinated patients with confirmed SARS-CoV-2 infection (13 mild, 218 moderate, 48 severe) were enrolled. Peripheral lymphocyte subsets were analyzed by flow cytometry at admission and at 50 days post-symptom onset (DPSO 50).ResultsTotal T-cell counts normalized in 90–98% of patients in the moderate and severe groups by DPSO 50. Nevertheless, a subgroup exhibited persistent B-cell lymphopenia (<90 cells/µL) in 7.3% of moderate cases (median 77.1 cells/µL, IQR 51.9–83.8) and 12.5% of seltvere cases (median 54.5 cells/µL, IQR 28.4–79.3). Patients with B-cell deficiency also showed concurrent reductions in total T cells, CD4+ T cells, and CD4+CD25+CD127low/FOXP3+ regulatory T cells (Tregs). In moderate cases, CD4+ T cell and Treg counts correlated positively (r = 0.72, p < 0.001), independent of B-cell status, whereas this relationship was absent in severe cases, indicating severity-dependent immune dysregulation.ConclusionsApproximately 7–12% of moderate-to-severe COVID-19 survivors displayed persistent lymphopenia affecting B cells, CD4+ T cells, and Tregs at ~50 days post-symptom onset. These findings highlight distinct recovery trajectories and provide insights into Long COVID pathogenesis that may inform therapeutic strategies.

Background: End-stage renal disease (ESRD) is a growing global health concern, and hemodialysis (HD) remains the most common life-sustaining therapy for patients with advanced kidney failure. Both humoral and cellular immunity are impaired post hemodialysis, leading to immune system dysfunction. Methods: We utilized flow cytometry to quantify cell populations based on surface markers, including CD3 (total T lymphocytes), CD4 (helper T-cells), CD8 (cytotoxic T-cells), CD19 (B lymphocytes), and CD16/CD56 (natural killer (NK) cells). EDTA-blood samples were collected intravenously immediately before and after dialysis. Results: A consistent decline in CD3+ T lymphocytes was observed post hemodialysis. This reduction occurred across both male and female cohorts: p = 0.0342 and p = 0.0002, respectively. CD8+ cytotoxic T-cells decreased significantly post HD, p = 0.0003. Conversely, CD4+ helper T-cells exhibited a paradoxical increase, p = 0.0321. The divergent trends in CD4+ and CD8+ cells led to a statistically significant increase in the CD4/CD8 ratio post dialysis, p = 0.0005. Notably, stratification by gender uncovered that the post-HD changes in CD4+ and CD8+ T-cells were exclusive to female patients. Females demonstrated a pronounced increase in CD4+ cells and a sharper decline in CD8+ cells compared to males. CD19+ B lymphocytes showed a statistically significant decline post hemodialysis (p < 0.0001). While both genders exhibited reduced B-cell percentages, female patients experienced a more pronounced reduction than males. NK cells were severely depleted post dialysis in both male and female cohorts. Conclusions: Overall, the immune alterations observed in HD patients, including T-cell reduction, B-cell lymphopenia, and changes in NK cell populations, contribute to the increased risk of infections, malignancy, and cardiovascular disease in this population.

Allogeneic hematopoietic stem cell transplantation in a patient with combined immunodeficiency caused by IRF4 mutation.

Abstract We present a case of recalcitrant eczema in a patient with B-cell and natural killer (NK) cell lymphopenia of unknown cause. A 53-year-old man was referred to the dermatology clinic with a 6-month history of an itchy erythematous rash, starting on his chest and arms and spreading to involve his back and legs. This was causing significant disruption to sleep and work. He had tried superpotent topical corticosteroids and oral prednisolone, as well as emollients, none of which had improved his symptoms. He had no personal or family history of skin disease. He had been well without a significant medical history until 7 years ago, when he had developed recurrent chest infections and an episode of confirmed multidermatomal shingles. On examination, he was suberythrodermic with a widespread erythematous, polymorphic rash that was eczematous in some areas but raised and annular in others. Initially, we were concerned about mycosis fungoides; however, Sézary cells were not detected on flow cytometry and skin biopsies demonstrated findings consistent with atopic dermatitis. We conducted lymphocyte subset testing because of his atypical infection history, which demonstrated complete absence of B cells and low NK cells (0.02 × 109 cells L−1). He had low IgM and IgA levels, but normal IgG levels. We therefore treated him as having eczema and additionally referred him to the immunology team. Initial treatment with mometasone ointment was then escalated with clobetasol propionate and tacrolimus 0.1%, but with no beneficial effect. Narrowband ultraviolet B therapy over 3 months also did not improve his symptoms. He was investigated by the immunologists, who were unable to find any cause for his lymphopenia. He had normal Bruton tyrosine kinase expression, a myeloid gene panel did not detect mutations in GATA2 and UBA1, and whole-genome sequence analysis did not identify any pathogenic variant(s) that could explain the cause of his clinical presentation. He had no history of prior immunosuppressive treatment and no evidence of thymoma on computed tomography imaging. As his eczema was refractory to both topical treatments and phototherapy, we wanted to start systemic treatment but were limited with options that would not further compound his immunosuppression. Tralokinumab was trialled for 12 weeks, as this has a single therapeutic target (interleukin-13), but unfortunately there was no improvement. Following discussion with the immunologists, he was commenced on upadacitinib as this was felt to have a more targeted immunosuppressive effect above agents such as methotrexate and dupilumab. We await his next follow-up appointment to assess response. This case highlights the complexity of treating an immunocompromised individual with immunosuppressive agents, when the cause of their immunosuppression is unknown.

Before the implementation of newborn screening (NBS), only a few cases of agammaglobulinemia associated with IGLL1 variants had been reported. The IGLL1 gene encodes the surrogate light chain components λ5 and VpreB, which form a crucial part of the pre-B cell receptor complex. A recently published study reported 17 cases of agammaglobulinemia caused by IGLL1 variants, the vast majority of which were identified through NBS. Here, we report two cases of B-cell lymphopenia along with IGLL1 variants identified through NBS in Ukraine. Both neonates had undetectable KREC and normal TREC levels at birth. Despite the presence of B-cell lymphopenia, only one patient exhibited a transient decline in IgG levels. IgA and IgM levels remained normal during the first year of follow-up, which had not been reported in previous IGLL1 cases. Both children presented with mild upper respiratory tract infections. Genetic analysis revealed that both patients carried the c.425C &amp;gt; T variant, with one patient also harboring the c.258del variant. These variants have been linked to B-cell lymphopenia and low KREC levels in prior studies. Two additional variants were identified on the second chromosome: c.368C &amp;gt; G, which is predicted to be tolerated, and c.377T &amp;gt; C, which is likely disruptive. This study highlights the potential underdiagnosis of B-cell lymphopenia caused by IGLL1 variants. Moreover, the comparison between clinically diagnosed cases and those identified through NBS underscores the importance of early diagnosis that facilitates close monitoring of affected patients from birth, timely initiation of immunoglobulin replacement therapy, and the prevention of complications and severe manifestations.

IntroductionSevere combined immunodeficiency (SCID) and other profound T- and B-cell lymphopenias are life-threatening conditions that benefit from early diagnosis and treatment. In October 2022, Ukraine launched a nationwide newborn screening (NBS) program for SCID using the T-cell receptor excision circle/kappa-deleting recombination excision circle/spinal muscular atrophy (TREC/KREC/SMA) assay, despite ongoing war-related challenges. The aim of this study was to analyze the results of the SCID NBS program in Ukraine, evaluate its effectiveness, and outline the current challenges and future directions for its development.MethodsWe analyzed data of screened newborns for SCID and related lymphopenias using the TREC/KREC/SMA assay from October 2022 to April 2025. The results of lymphocyte flow cytometry values, genetic testing, and clinical management of patients with positive TREC/KREC results were evaluated.ResultsAmong 398,415 screened newborns, 57 were identified with positive results (32 TREC ± KREC and 25 only KREC). The program demonstrated a high diagnostic yield, with an overall referral rate of 0.01%. In total, 18 newborns with inborn errors of immunity were diagnosed due to NBS (7 SCID/leaky SCID and 11 non-SCID). One case of ZAP70 deficiency was missed due to normal levels of T cells. The incidence of SCID/leaky SCID detected by NBS was 1 in 57,000 live births, and 1 in 49,800 live births when all diagnosed cases, including one initially missed case, were taken into account, which is comparable to data from other countries. All patients with SCID/leaky SCID identified by NBS received hematopoietic stem cell transplantation, with a survival rate of 85.7%. Nijmegen breakage syndrome was the most common syndromic cause of non-SCID T-cell lymphopenias (three cases). The use of the KREC assay enabled the first-time identification in Ukraine of B-cell lymphopenias associated with variants in IGLL1 gene.ConclusionsThe nationwide NBS program in Ukraine demonstrated high sensitivity and specificity in detecting SCID, with a low referral rate and high survival rates among diagnosed patients.

Long COVID (LC) poses a persistent challenge in clinical practice due to limited understanding of its etiology. LC is hypothesized to stem from aberrant immune responses in COVID-19. Vaccinations, which boost immune cells to restore function, could help ease LC symptoms. To exclude the impact of vaccination, we examined the immune cell profiles of recovering COVID-19 patients before vaccines were available. White blood cell differentials were monitored in ninety-twohealthy unvaccinated controls. Seventy-six unvaccinated COVID-19 patients were monitored upon admission and on the 50th day post-symptom onset (DPSO50). Peripheral lymphocyte subsets were analyzed using flow cytometry. Mild cases showed no significant changes in lymphocyte counts or subsets from admission to DPSO50. By DPSO50, severe and critical cases showed almost complete recovery from lymphopenia, with critical cases having CD19+ B-cell counts approximately 45% lower than the mild group. Severe and critical cases exhibited reduced B-cell frequencies, with critical cases displaying around 48% higher natural killer (NK) cell counts. In mild cases, NK cell counts negatively correlated with B-cell counts (r=-0.528, p=0.02). Additionally, critical cases showed positive correlations between NK cell counts and CD4+ T-cell counts (r=0.83, p<0.01), and between NK cell counts and CD8+ T-cell counts (r=0.74, p<0.01). Severe cases demonstrated decreased counts of CD4+CD25+CD127lowFoxP3+ regulatory T-cells (Tregs), which positively correlated with B-cell counts (r=0.37, p<0.05). Our findings indicate that aberrant immune cell profiles in COVID-19 patients change dynamically during recovery, depending on disease severity. This study suggests that convalescent patients from critical COVID-19 may experience long-lasting B-cell lymphopenia.

WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome is an ultra-rare, combined primary immunodeficiency and chronic neutropenic disorder characterized by a range of clinical presentations, including peripheral neutropenia, lymphopenia, and recurrent infections. WHIM syndrome is most often caused by gain-of-function mutations in the gene encoding C-X-C chemokine receptor 4 (CXCR4). As such, inhibition of CXCR4 with XOLREMDI® (mavorixafor), an orally bioavailable CXCR4 antagonist, demonstrated clinically meaningful increases in absolute neutrophil and lymphocyte counts and concomitant reduction in infections in patients with WHIM syndrome, resulting in its recent U.S. Food and Drug Administration approval. The impact of CXCR4 antagonism on other aspects of the pathobiology in WHIM syndrome, such as lymphopoiesis and leukocyte trafficking between primary and secondary lymphoid organs, is less understood. In the current study, the effects of CXCR4 antagonism on leukocyte trafficking and distribution in primary and secondary lymphoid organs were investigated in a mouse model of WHIM syndrome carrying the heterozygous Cxcr41013 mutation. Cxcr4+/1013 and Cxcr4 wild-type mice received the orally bioavailable CXCR4 antagonist X4-185. Blood, spleen and bone marrow samples were collected for numeration, flow cytometry, and functional studies. Cxcr4+/1013 mice exhibited profound peripheral blood leukopenia as seen in patients with WHIM syndrome. CXCR4 antagonism corrected circulating leukopenia and mobilized functional neutrophils without disrupting granulopoiesis in the bone marrow of Cxcr4+/1013 mice. Furthermore, Cxcr4+/1013 displayed aberrant splenic T and B-cell counts and frequency. Treatment with X4-185 normalized splenic T-cell abnormalities, correcting the reduced CD8+ T-cell numbers, restoring the CD4/CD8 T-cell ratio, and ameliorating peripheral blood T-cell lymphopenia. In addition, CXCR4 antagonism was able to correct the abnormal frequencies and numbers of splenic marginal zone and follicular B cells in Cxcr4+/1013 mice, and ultimately normalize B-cell lymphopenia in the peripheral circulation. Our study provides comprehensive evidence that oral dosing with a CXCR4 antagonist can effectively correct WHIM-associated neutrophil and lymphocyte abnormalities in a mouse model of WHIM syndrome. These findings extend our understanding of how targeting the dysregulated CXCR4 signaling pathway can ameliorate the pathogenesis of WHIM syndrome.

Mutations in the human nuclear factor-κB2 gene (NFKB2) are associated with common variable immunodeficiency (CVID) or combined immunodeficiency diseases (CID), characterized by B-cell lymphopenia, hypogammaglobulinemia, and T-cell dysfunction. This study investigated whether B cells with NFKB2 mutations exhibit intrinsic impairments in activation, class-switch recombination, and differentiation. We analyzed five patients from four unrelated families with CVID, each carrying a heterozygous NFKB2 mutation: P1 (C.2595_2614del, p.A867Gfs*12), P2 (C.2597G > A, p.S866N), P3 (C.2540dupT, p.R848Efs*38), and P4 and P5 (C.2570_2571insCAGCACA, p.A860Qfs*28). The patients with frameshift mutations (P1, P3, P4, and P5) exhibited truncated proteins detectable in their peripheral blood mononuclear cells, while P2 had a missense mutation. All identified mutations disrupted the processing of p100 into the active p52 form, resulting in NF-κB2 loss of function and IκBδ gain of function. Clinically, P1, P2, and P3 exhibited B-cell lymphopenia, and all five patients presented with hypogammaglobulinemia. Notably, P2 exhibited a markedly low B-cell count, associated with increased proportions of memory B and IgD-CD27- double-negative B cells. In vitro experiments with naïve B cells from P1 and P4 demonstrated decreased survival, impaired activation, and reduced differentiation into CD27+IgD- cells and plasmablasts, while class-switch recombination was unaffected. These findings reveal novel B-cell intrinsic functional defects in patients with NFKB2 mutations.

ObjectiveMechanisms underpinning clinical evolution to systemic lupus erythematosus (SLE) from preceding antinuclear antibodies (ANA) positivity are poorly understood. This study aimed to understand blood immune cell transcriptional signatures associated with...

PI4KA-related disorder is a highly clinically variable condition characterized by neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus) and gastrointestinal (inflammatory bowel disease and multiple intestinal atresia) manifestations. Although features consistent with immunodeficiency (autoimmunity/autoinflammation and recurrent infections) have been reported in a subset of patients, the burden of B-cell deficiency and hypogammaglobulinemia has not been extensively investigated. We sought to describe the clinical presentation and manifestations of patients with PI4KA-related disorder and to investigate the metabolic consequences of biallelic PI4KA variants in B cells. Clinical data from patients with PI4KA variants were obtained. Multi-omics analyses combining transcriptome, proteome, lipidome and metabolome analyses in conjunction with functional assays were performed in EBV-transformed B cells. Clinical and laboratory data of 13 patients were collected. Recurrent infections (7/13), autoimmune/autoinflammatory manifestations (5/13), B-cell deficiency (8/13) and hypogammaglobulinemia (8/13) were frequently observed. Patients' B cells frequently showed increased transitional and decreased switched memory B-cell subsets. Pathway analyses based on differentially expressed transcripts and proteins confirmed the central role of PI4KA in B cell differentiation with altered B-cell receptor (BCR) complex and signalling. By altering lipids production and tricarboxylic acid cycle regulation, and causing increased endoplasmic reticulum stress, biallelic PI4KA mutations disrupt B cell metabolism inducing mitochondrial dysfunction. As a result, B cells show hyperactive PI3K/mTOR pathway, increased autophagy and deranged cytoskeleton organization. By altering lipid metabolism and TCA cycle, impairing mitochondrial activity, hyperactivating mTOR pathway and increasing autophagy, PI4KA-related disorder causes a syndromic inborn error of immunity presenting with B-cell deficiency and hypogammaglobulinemia.

Common variable immunodeficiency (CVID) is considered the most symptomatic type of inborn errors of immunity in humans. Along with infectious complications, which have numerous consequences, noninfectious complications are a major challenge among CVID patients. All CVID patients registered in the national database were included in this retrospective cohort study. Patients were divided into 2 groups based on the presence of B-cell lymphopenia. Demographic characteristics, laboratory findings, noninfectious organ involvement, autoimmunity, and lymphoproliferative diseases were evaluated. Among 387 enrolled patients, 66.4% were diagnosed with noninfectious complications and 33.6% with isolated infectious presentations. Enteropathy, autoimmunity, and lymphoproliferative disorders were reported in 35.1%, 24.3%, and 21.4% of patients, respectively. Some complications, including autoimmunity and hepatosplenomegaly, were reported to be significantly more frequent among patients with B-cell lymphopenia. As for organ involvement, the dermatologic, endocrine, and musculoskeletal systems were predominantly affected in CVID patients with B-cell lymphopenia. Among autoimmune manifestations, the frequency of rheumatologic, hematologic, and gastrointestinal autoimmunity was reported to be higher than that of other types of autoimmunity not associated with B cell-lymphopenia. Furthermore, hematological cancers, particularly lymphoma, were the most common type of malignancy. The mortality rate was 24.5%, and respiratory failure and malignancies were the most common causes of death, with no significant differences between the 2 groups. Considering that some of the noninfectious complications might be associated with B-cell lymphopenia, regular patient monitoring and follow-up with proper medication (in addition to immunoglobulin replacement therapy) are highly recommended to prevent sequelae and increase patient quality of life.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome is a rare disease caused by biallelic mutations of the AIRE gene, usually presenting with the triad hypoparathyroidism-adrenal failure-chronic mucocutaneous candidiasis (CMC) and nonendocrine manifestations. The aim of this study was to determine the molecular profile of the AIRE gene, the prevalence of rare manifestations, and to characterize immunological disturbances in a French cohort. A national, multicenter prospective observational study to collect genetic, clinical, biological, and immunological data (NCT03751683). Twenty-five patients (23 families) were enrolled. Eleven distinct AIRE variants were identified, 2 of which were not previously reported: an intronic variant, c.653-70G > A, and a c.1066del (p.Arg356GlyfsX22) variant (exon 9). The most common was the Finnish variant c.769C > T (16 alleles), followed by the variant c.967_979del13 (15 alleles), which seemed associated with a less severe phenotype. Seventeen out of 25 patients were homozygote. The median number of clinical manifestations was 7; 19/25 patients presented with the hypoparathyroidism-adrenal failure-CMC triad, 8/13 showed pulmonary involvement, 20/25 had ectodermal dystrophy, 8/25 had malabsorption, and 6/23 had asplenia. Fifteen out of 19 patients had natural killer cell lymphopenia with an increase in CD4+ and CD8+ T lymphocytes and an age-dependent alteration of B lymphocyte homeostasis compared with matched controls (P < .001), related to the severity of the disease. All tested sera (n = 18) were positive for anti-interferon-α, 15/18 for anti-IL-22 antibodies, and 13/18 for anti-IL-17F antibodies, without clear phenotypic correlation other than with CMC. This first prospective cohort showed a high AIRE genotype variability, with 2 new gene variants. The prevalence of potentially life-threatening nonendocrine manifestations was higher with systematic screening. These manifestations could, along with age-dependent B-cell lymphopenia, contribute to disease severity. Systematic screening for all the manifestations of the syndrome would allow earlier diagnosis, supporting vaccination and targeted therapeutic approaches.

MYSM1 attenuates DNA damage signals triggered by physiologic and genotoxic DNA breaks

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system (CNS) caused by reactivation of the polyomavirus JC (JCV) typically in immunocompromised individuals. The risk of PML among rheumatic diseases may be higher for systemic lupus erythematosus (SLE), without, however, a clear association with the type and intensity of background therapy. We present the development and outcome of PML in a 32-year-old female lupus patient under mild immunosuppressive treatment, yet with marked B-cell lymphopenia in the peripheral blood and bone marrow (<1% of total lymphocytes). Despite treatment with the immune checkpoint inhibitor pembrolizumab, the patient showed progressive neurological and brain imaging deterioration and eventually died 15 months after PML diagnosis. To unveil possible underlying genetic liabilities, whole exome sequencing was performed which identified deleterious variants in GATA2 and CDH7 genes, which both have been linked to defective T- and/or B-lymphocyte production. These findings reiterate the possible role of disease-/patient-intrinsic factors, rather than that of drug-induced immunosuppression, in driving immune dysregulation and susceptibility to PML in certain patients with SLE.

MECOM deficiency is a recently identified inborn error of immunity and inherited bone marrow failure syndrome caused by haploinsufficiency of the hematopoietic transcription factor MECOM. It is unique among inherited bone marrow failure syndromes, many of which present during later childhood or adolescence, because of the early age of onset and severity of the pancytopenia, emphasizing the importance and gene dose dependency of MECOM during hematopoiesis. B-cell lymphopenia and hypogammaglobulinemia have been described in a subset of patients with MECOM deficiency. While the mechanisms underlying the B-cell deficiency are currently unknown, recent work has provided mechanistic insights into the function of MECOM in hematopoietic stem cell (HSC) maintenance. MECOM binds to regulatory enhancers that control the expression of a network of genes essential for HSC maintenance and self-renewal. Heterozygous mutations, as seen in MECOM-deficient bone marrow failure, lead to dysregulated MECOM network expression. Extra-hematopoietic manifestations of MECOM deficiency, including renal and cardiac anomalies, radioulnar synostosis, clinodactyly, and hearing loss, have been reported. Individuals with specific genotypes have some of the systemic manifestations with isolated mild thrombocytopenia or without hematologic abnormalities, highlighting the tissue specificity of mutations in some MECOM domains. Those infants with MECOM-associated bone marrow failure require HSC transplantation for survival. Here, we review the expanding cohort of patient phenotypes and accompanying genotypes resulting in MECOM deficiency, and the proposed mechanisms underlying MECOM regulation of human HSC maintenance and B-cell development.

B cell depletion in infants after intra uterine exposure to immunomodulating chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP): A case series and review of the literature