Inborn Errors of Immunity.

Inborn errors of immunity occur in 1 in 1000 to 1 in 5000 individuals and are characterized by immune deficiency and immune dysregulation. The primary care provider (PCP) should be familiar with key features of these diagnoses including recurrent and/or severe infections, hyperinflammation, malignancy, and autoimmunity and have a low threshold to refer for evaluation. The PCP can begin a laboratory evaluation before referral by sending a complete blood count (CBC) with differential, antibody levels, vaccine titers, and possibly other tests. Management approaches vary from antibiotic prophylaxis to hematopoietic stem cell transplantation depending on the specific diagnosis.

A Nationwide Study of the Delayed Diagnosis and the Clinical Manifestations of Predominantly Antibody Deficiencies and CTLA4-Mediated Immune Dysregulation Syndrome in Greece.

Background and Objectives: Predominantly antibody deficiencies (PAD) represent the most common type of primary immunodeficiencies in humans, characterized by a wide variation in disease onset, clinical manifestations, and outcome. Considering that the prevalence of PAD in Greece is unknown, and there is limited knowledge on the clinical and laboratory characteristics of affected patients, we conducted a nationwide study. Materials and Methods: 153 patients (male/female: 66/87; median age: 43.0 years; range: 7.0-77.0) diagnosed, and followed-up between August 1979 to September 2023. Furthermore, we classified our cohort into five groups according to their medical history, immunoglobulin levels, and CTLA4-mutational status: 123 had common variable immunodeficiency (CVID), 12 patients with "secondary" hypogammaglobulinemia due to a previous B-cell depletion immunotherapy for autoimmune or malignant disease several years ago (median: 9 years, range 6-14) displaying a typical CVID phenotype, 7 with combined IgA and IgG subclass deficiencies, 5 patients with CVID-like disease due to CTLA4-mediated immune dysregulation syndrome, and 6 patients with unclassified hypogammaglobulinemia. Results: We demonstrated a remarkable delay in PAD diagnosis, several years after the onset of related symptoms (median: 9.0 years, range: 0-43.0). A family history of PAD was only present in 11.8%, with the majority of patients considered sporadic cases. Most patients were diagnosed in the context of a diagnostic work-up for recurrent infections, or recurrent/resistant autoimmune cytopenias. Interestingly, 10 patients (5.6%) had no history of infection, diagnosed due to either recurrent/resistant autoimmunity, or during a work-up of their medical/family history. Remarkable findings included an increased prevalence of lymphoproliferation (60.1%), while 39 patients (25.5%) developed bronchiectasis, and 16 (10.5%) granulomatous disease. Cancer was a common complication in our cohort (25 patients, 16.3%), with B-cell malignancies representing the most common neoplasms (56.7%). Conclusion: Our findings indicate the necessity of awareness about PAD and their complications, aiming for early diagnosis and the appropriate management of affected patients.

Variable Syndromic Immunodeficiency in Patients with Biallelic PRIM1 Mutations.

Mutations in genes of the DNA polymerase complex have been linked to impaired immunological function next to distinct syndromic features. Biallelic mutations in PRIM1 are associated with a primordial dwarfism syndrome with variable hypogammaglobulinemia. The disease is mostly lethal in infancy due to pulmonary infections as well as hepatic cirrhosis. We studied 3 novel patients with PRIM1-deficiency with a focus on immunological consequences. All three shared dysmorphic features including a prominent forehead, triangular face and bilateral cryptorchidism. P1 carried the novel homozygous PRIM1 splice variant c.103+2T>G, allowing residual protein expression and associated with a mild clinical phenotype. P2 and P3 carried the known homozygous variant c.638+36C>G and died in infancy. Paradoxically, B cell lymphopenia was most pronounced in P1. No other significant lymphocyte abnormalities were detected. Interestingly, all 3 patients showed variable, but intermittently excessive Type I interferon signatures. In summary, the B-cell deficiency in PRIM1-deficiency is markedly variable and the severity of syndromic manifestations is not predictive of the immunological phenotype. We highlight a potential contribution of pathological type I interferon activation to disease pathogenesis which warrants further investigations.

ZAP-70 mutation: a case with familial autoimmune haemolytic anaemia and immune deficiency.

Zeta-chain associated protein kinase 70 kDa (ZAP-70) deficiency is one of the rare immunodeficiency disorders due to autosomal recessive homozygous or compound heterozygous loss-of-function mutations in the ZAP-70 GENE In the literature, patients with ZAP-70 deficiency have been reported with a broad spectrum of clinical manifestations including recurrent respiratory infections (81.8%), cutaneous involvement (57.9%), lymphoproliferation (32.4%), autoimmunity (19.4%), enteropathy (18.4%) and increased risk of malignancies (8.1%). The most common immunological phenotype in those patients was low CD8+ T cell counts (97.9%) and normal non-functioning CD4+ T cell. Haematopoietic stem cell transplantation was applied as a curative treatment for this disorder.

Periodontal disease in patients with WHIM syndrome.

AIM: WHIM (warts, hypogammaglobulinaemia, infections and myelokathexis) syndrome is a rare combined primary immunodeficiency disease caused by gain-of-function (GOF) mutations in the chemokine receptor CXCR4 and includes severe neutropenia as a common feature. Neutropenia is a known risk factor for periodontitis; however, a detailed periodontal evaluation of a WHIM syndrome cohort is lacking. This study aimed to establish the evidence base for the periodontal status of patients with WHIM syndrome. MATERIALS AND METHODS: Twenty-two adult WHIM syndrome patients and 22 age- and gender-matched healthy volunteers (HVs) were evaluated through a comprehensive medical and periodontal examination. A mouse model of WHIM syndrome was assessed for susceptibility to naturally progressing or inducible periodontitis. RESULTS: Fourteen patients with WHIM syndrome (63.6%) and one HV (4.5%) were diagnosed with Stage III/IV periodontitis. No WHIM patient presented with the early onset, dramatic clinical phenotypes typically associated with genetic forms of neutropenia. Age, but not the specific CXCR4 mutation or absolute neutrophil count, was associated with periodontitis severity in the WHIM cohort. Mice with a Cxcr4 GOF mutation did not exhibit increased alveolar bone loss in spontaneous or ligature-induced periodontitis. CONCLUSIONS: Overall, WHIM syndrome patients presented with an increased severity of periodontitis despite past and ongoing neutrophil mobilization treatments. GOF mutations in CXCR4 may be a risk factor for periodontitis in humans.

Evaluation of the Effectiveness of the 6 Warning Signs of the European Society for Immunodeficiencies for Primary Immunodeficiencies in Older Adults.

INTRODUCTION: Diagnostic delay in cases of primary immunodeficiency (PID) is a significant problem for clinicians, and most do not have sufficient awareness of this uncommon disorder. The European Society for Immunodeficiencies (ESID) has developed 6 warning signs to increase awareness of adult PIDs. The aim of this study was to determine the prevalence of PID in older adults regardless of the reason for presentation and to evaluate the effectiveness of the 6 warning signs of ESID in the diagnosis of PIDs. METHODS: The study included 1,331 patients aged ≥65 years who presented at our clinic for any reason and were questioned about the ESID 6 warning signs for PIDs. After the exclusion of reasons for secondary immunodeficiency (SID), all the patients underwent immunological evaluation for the diagnosis of potential underlying PIDs. RESULTS: After excluding 6 patients diagnosed with SID, PID was diagnosed in 16 (1.2%) of 1,325 older adults using ESID warning signs. The most common reasons for presentation were infection (69%) in the PID group and urticaria and/or angioedema (41.5%) in the non-PID group. The most common PID subgroup was common variable immunodeficiency (50%). In 12 of the patients diagnosed with PID, there was at least 1 positive ESID warning sign. In 4 patients, PID was determined despite negative ESID warning signs. The patients diagnosed with PID showed a significant, minimal level of agreement with questions 1 and 4 of the ESID warning signs (p < 0.001, ĸ = 0.204, p = 0.005, ĸ = 0.208, respectively). CONCLUSION: The ESID warning signs do not encompass all the symptoms and findings of PIDs. There is a need for more infection-centered questions to determine PIDs in older adults. Therefore, the ESID warning signs should be further developed.

Spectrum of Primary Immunodeficiency Disorders in Hospitalized Children: Multicentric Data From Kolkata.

OBJECTIVE: To evaluate the incidence and types of primary immunodeficiency diseases (PIDs) in hospitalized children with infection. METHODS: This prospective study was conducted in five tertiary-care facilities in Kolkata over two consecutive years between November 1, 2018 and October 31, 2020. We included all children aged upto 12years who were hospitalized and screened them for PID. Children were screened for suspected IPD using Jeffrey Modell Foundation (JMF) Criteria; any child who satisfied at least 2 out of 10 warning signs was further evaluated for PIDs. RESULTS: Out of 33,204 hospital admissions, 50 children satisfied JMF criteria. Out of 50 children screened during the study period, 27 were finally diagnosed with an underlying PID, with a prevalence of 1 in 1000 hospitalized children. Majority (37.03%) of them had antibody deficiency followed by phagocytic defect (33.3%). Chronic granulomatous disease was the commonest PID followed by common variable immunodeficiency. Around 62.97% children presented with respiratory infections and overall Acinetobacter baumannii was the commonest isolated organism. CONCLUSION: Our study presents the first cohort of PID from eastern India. A methodical step-wise clinical and diagnostic approach can facilitate early diagnosis and timely therapeutic interventions.

Multiple intracellular pathogen infections with ocular pathologies associated with adult-onset immunodeficiency due to anti-interferon-γ autoantibodies: a case report.

BACKGROUND: Autoantibodies against interferon-γ (IFN-γ) can inhibit IFN-γ-dependent signal transducer and activator of transcription 1 phosphorylation and thus increase the risk of infection with intracellular pathogens, such as Talaromyces marneffei (TM), nontuberculous mycobacteria (NTMs), and Mycobacterium tuberculosis (TB). Here, we report a rare case of triple infection caused by TM, NTM, and TB in a human immunodeficiency virus-negative patient. CASE PRESENTATION: A middle-aged female was admitted to our hospital after experiencing recurrent rash, cough, and expectoration for 4 months. She was successively diagnosed with NTM, TM, and TB infections without conventional immunosuppression-associated factors. However, after effective anti-infective treatment, the patient was confirmed to have allergic conjunctivitis and was successfully treated with corticosteroids and immunosuppressants. The most conspicuous characteristics were recurrent infection and immune disorders. CONCLUSIONS: High-titer anti-IFN-γ autoantibodies are strongly associated with severe and disseminated infections, such as NTM, TM, and TB. It is characterized by persistently high degree of inflammation and high immunoglobin levels.

The Association Between Malignancy, Immunodeficiency, and Atopy in IgE-Deficient Patients.

BACKGROUND: Studies show that IgE-deficient patients (IgE <2.5 kU/L) have a high prevalence of malignancy, but relevant clinical and laboratory characteristics associated with this susceptibility have never been well characterized. OBJECTIVE: To evaluate if there is an association between a malignancy diagnosis and other immunological parameters (atopy or other immune abnormalities) in IgE-deficient patients. METHODS: We retrospectively analyzed medical records of 408 IgE-deficient adults seen at our institution between 2005 and 2020. RESULTS: A malignancy diagnosis was found in 23.5% (96 of 408) of IgE-deficient patients. Among those who had allergy skin testing performed for allergic rhinitis-like symptoms, the nonatopic IgE-deficient patients (negative environmental skin tests) were more likely to have a malignancy diagnosis than the atopic group (odds ratio [OR] = 4.36, 95% confidence interval [CI]: 1.11-17.13, P = .03). The IgE-deficient individuals with an additional non-common variable immunodeficiency (non-CVID) humoral abnormality (n = 75; with low IgG, IgA, or IgM without meeting criteria for CVID) were more likely to have a malignancy diagnosis than those with only a selective IgE deficiency (n = 134; with normal IgA, IgM, and IgG) (OR = 2.79, 95% CI: 1.37-5.68, P = .005). Among the IgE-deficient patients, certain less well-defined immune abnormalities such as IgM deficiency (OR = 2.46, 95% CI: 1.13-5.36, P = .02), IgG2 deficiency (OR = 10.14, 95% CI: 1.9-54.1, P = .007), and CD4 lymphopenia (OR = 7.81, 95% CI: 2.21-27.63, P = .001) were associated with higher malignancy odds than those without these abnormalities. CONCLUSION: The odds of a malignancy diagnosis are not shared equally by all IgE-deficient patients. Prospective studies are needed to determine the utility of performing skin testing and measuring additional immunological parameters in assessing the long-term malignancy risk in IgE-deficient patients.

Combined Immunodeficiency Caused by a Novel Nonsense Mutation in LCK.

Mutations affecting T-cell receptor (TCR) signaling typically cause combined immunodeficiency (CID) due to varying degrees of disturbed T-cell homeostasis and differentiation. Here, we describe two cousins with CID due to a novel nonsense mutation in LCK and investigate the effect of this novel nonsense mutation on TCR signaling, T-cell function, and differentiation. Patients underwent clinical, genetic, and immunological investigations. The effect was addressed in primary cells and LCK-deficient T-cell lines after expression of mutated LCK. RESULTS: Both patients primarily presented with infections in early infancy. The LCK mutation led to reduced expression of a truncated LCK protein lacking a substantial part of the kinase domain and two critical regulatory tyrosine residues. T cells were oligoclonal, and especially naïve CD4 and CD8 T-cell counts were reduced, but regulatory and memory including circulating follicular helper T cells were less severely affected. A diagnostic hallmark of this immunodeficiency is the reduced surface expression of CD4. Despite severely impaired TCR signaling mTOR activation was partially preserved in patients' T cells. LCK-deficient T-cell lines reconstituted with mutant LCK corroborated partially preserved signaling. Despite detectable differentiation of memory and effector T cells, their function was severely disturbed. NK cell cytotoxicity was unaffected. Residual TCR signaling in LCK deficiency allows for reduced, but detectable T-cell differentiation, while T-cell function is severely disturbed. Our findings expand the previous report on one single patient on the central role of LCK in human T-cell development and function.

Inherited Human BCL10 Deficiencies.

Human BCL10 deficiency causes combined immunodeficiency with bone marrow transplantation as its only curative option. To date, there are four homozygous mutations described in the literature that were identified in four unrelated patients. Here, we describe a fifth patient with a novel mutation and summarize what we have learned about BCL10 deficiency. Due to the severity of the disease, accurate knowledge of its clinical and immunological characteristics is instrumental for early diagnosis and adequate clinical management of the patients.

Evaluation of Clinical and Immunological Alterations Associated with ICF Syndrome.

PURPOSE: Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive combined immunodeficiency. The detailed immune responses are not explored widely. We investigated known and novel immune alterations in lymphocyte subpopulations and their association with clinical symptoms in a well-defined ICF cohort. METHODS: We recruited the clinical findings from twelve ICF1 and ICF2 patients. We performed detailed immunological evaluation, including lymphocyte subset analyses, upregulation, and proliferation of T cells. We also determined the frequency of circulating T follicular helper (cTFH) and regulatory T (Treg) cells and their subtypes by flow cytometry. RESULTS: There were ten ICF1 and two ICF2 patients. We identified two novel homozygous missense mutations in the ZBTB24 gene. Respiratory tract infections were the most common recurrent infections among the patients. Gastrointestinal system (GIS) involvements were observed in seven patients. All patients received intravenous immunoglobulin replacement therapy and antibacterial prophylaxis; two died during the follow-up period. Immunologically, CD4+ T-cell counts, percentages of recent thymic emigrant T cells, and naive CD4+ T decreased in two, five, and four patients, respectively. Impaired T-cell proliferation and reduced CD25 upregulation were detected in all patients. These changes were more prominent in CD8+ T cells. GIS involvements negatively correlated with CD3+ T-, CD3+CD4+ T-, CD16+CD56+ NK-cell counts, and CD4+/CD8+ T-cell ratios. Further, we observed expanded cTFH cells and reduced Treg and follicular regulatory T cells with a skewing to a TH2-like phenotype in all tested subpopulations. CONCLUSION: The ICF syndrome encompasses various manifestations affecting multiple end organs. Perturbed T-cell responses with increased cTFH and decreased Treg cells may provide further insight into the immune aberrations observed in ICF syndrome.

In-depth blood immune profiling of Good syndrome patients.

Introduction: Good syndrome (GS) is a rare adult-onset immunodeficiency first described in 1954. It is characterized by the coexistence of a thymoma and hypogammaglobulinemia, associated with an increased susceptibility to infections and autoimmunity. The classification and management of GS has been long hampered by the lack of data about the underlying immune alterations, a controversy existing on whether it is a unique diagnostic entity vs. a subtype of Common Variable Immune Deficiency (CVID). Methods: Here, we used high-sensitive flow cytometry to investigate the distribution of up to 70 different immune cell populations in blood of GS patients (n=9) compared to age-matched CVID patients (n=55) and healthy donors (n=61). Results: All 9 GS patients displayed reduced B-cell counts -down to undetectable levels (<0.1 cells/µL) in 8/9 cases-, together with decreased numbers of total CD4+ T-cells, NK-cells, neutrophils, and basophils vs. age-matched healthy donors. In contrast, they showed expanded TCRγδ+ T-cells (p ≤ 0.05). Except for a deeper B-cell defect, the pattern of immune cell alteration in blood was similar in GS and (age-matched) CVID patients. In depth analysis of CD4+ T-cells revealed significantly decreased blood counts of naïve, central memory (CM) and transitional memory (TM) TCD4+ cells and their functional compartments of T follicular helper (TFH), regulatory T cells (Tregs), T helper (Th)2, Th17, Th22, Th1/Th17 and Th1/Th2 cells. In addition, GS patients also showed decreased NK-cell, neutrophil, basophil, classical monocyte and of both CD1c+ and CD141+ myeloid dendritic cell counts in blood, in parallel to an expansion of total and terminal effector TCRγδ+ T-cells. Interestingly, those GS patients who developed hypogammaglobulinemia several years after the thymoma presented with an immunological and clinical phenotype which more closely resembled a combined immune humoral and cellular defect, with poorer response to immunoglobulin replacement therapy, as compared to those in whom the thymoma and hypogammaglobulinemia were simultaneously detected. Discussion: Our findings provide a more accurate definition of the immune cell defects of GS patients and contribute to a better discrimination among GS patients between those with a pure B-cell defect vs. those suffering from a combined immunodeficiency with important consequences on the diagnosis and management of the disease.

EXTL3-Associated Immunoskeletal Dysplasia with Neurodevelopmental Abnormalities: A Lethal Phenotype.

Background: Immunoskeletal dysplasia with neurodevelopmental abnormalities (ISDNA) caused by Exostosin-Like Glycosyltransferase 3 (EXTL3) biallelic mutations is a very rare syndrome with only 16 cases reported in the literature. Skeletal dysplasia, neurodevelopmental delay, immunodeficiency, liver, and kidney cysts are the most common findings of this syndrome. Case Presentation: Here, we report on a patient who exhibited a lethal phenotype with clinical characteristics of this syndrome and had a homozygous pathogenic mutation in EXTL3 gene. Conclusions: ISDNA should be kept in mind in the differential diagnosis of patients presenting with neuro-immuno-skeletal dysplasia phenotype.

[Should we suspect immune deficiency in internal medicine hospitalized patients?] / Quand suspecter une immunodéficience chez le patient hospitalisé en médecine interne?

Although often overlooked immune deficiencies are more common than generally believed. The internist is frequently the first physician to potentially meet affected patients, playing a significant role in detecting these immune deficiencies, whether they are primary (congenital) or secondary (acquired). In both scenarios, early identification and intervention can greatly reduce the morbidity and mortality of these patients. In this article, we review common immune deficits, suggest initial assessments when indicative signs are present, and provide guidance for management.

Les déficits immunitaires, quoique souvent méconnus, sont plus fréquents qu'on ne le pense. L'interniste est fréquemment le premier médecin à entrer en contact avec des patients potentiellement atteints, jouant ainsi un rôle important dans la détection de ces maladies, qu'elles soient primaires (congénitales) ou secondaires (acquises). Dans les deux cas, une identification et une intervention précoces peuvent considérablement réduire la morbidité et la mortalité de ces patients. Dans cet article, nous passons en revue les déficits immuns fréquents, suggérons des bilans initiaux en présence de signes évocateurs et fournissons des orientations pour la prise en charge.