CTLA-4 Deficiency Research Articles

2q33 Deletions Underlying Syndromic and Non-syndromic CTLA4 Deficiency.

CTLA4 deficiency is an inborn error of immunity (IEI) due to heterozygosity for germline loss-of-function variants of the CTLA4 gene located on chromosome 2q33.2. CTLA4 deficiency underlies pleiotropic immune and lymphoproliferation-mediated features with incomplete penetrance. It has been identified in hundreds of patients but copy number variants (CNVs) have been reported in only 12 kindreds, including nine which displayed large 2q33.1-2q33.2 deletions encompassing CTLA4. We conducted a nationwide study in France to identify patients with 2q33 deletions encompassing CTLA4. We investigated the clinical and immunological phenotypes and genotypes of these patients. We identified 12 patients across six unrelated kindreds with clinical immunodeficiency. Neurological features were recorded in three patients, including one with syndromic neurodevelopmental disorder. Single-nucleotide polymorphism (SNP) or comparative genomic hybridization (CGH) array analysis, and targeted high-throughput sequencing revealed five different heterozygous 2q33 deletions of 26 kilobases to 7.12 megabases in size and encompassing one to 41 genes.We identified a contiguous gene syndrome (CGS) due to associated KLF7 deficiency in a kindred with a neurodevelopmental phenotype. Deletions within the 2q33 region encompassing CTLA4 are rare and not extensively explored, and are probably underdiagnosed in cytogenetic practice. A literature review identified 14 different CGS loci including at least one gene responsible for an IEI. The deletions involved in IEIs should be systematically delimited, to facilitate screening for CGS.

Renegotiation, uncertainty, imagination: Assemblage perspectives on reproductive and family planning with an Inborn Error of immunity

Advances within the new genetics expand our understanding of the scope and presentation of inherited conditions, particularly to include incompletely penetrant and variably expressive conditions. These features can complicate patients’ reproductive and family planning processes, in part because they expand the possibilities of life with an inherited condition. Despite many inquiries into reproductive planning with an inherited condition, accounts of experiential knowledge and reproductive planning fail to adequately describe the uncertainties experienced by people living with incompletely penetrant and variably expressive conditions. To address this gap, we conducted a qualitative, cross-sectional study using assemblage theory to characterize the impacts of experiential knowledge on reproductive planning for individuals living with Inborn Errors of Immunity (IEI) that exhibit incomplete penetrance and variable expressivity.Eligible participants were between ages 18 and 48, with a diagnosis of either GATA2 deficiency, PIK3CD gain-of-function disorder, or CTLA4 deficiency. Using an abductive thematic approach, attention was paid to the people, ideas, and non-human objects embedded within participants’ accounts of disease experience and reproductive planning. Organized around the objects of genetic diagnosis, the body, and hypothetical children, this analysis illustrates how disease can be conceptualized as an assemblage of human and non-human objects which provoke numerous actions and affective engagements in reproductive planning. These engagements include renegotiation, uncertainty, and imagination. By emphasizing the distribution of agency and action across systems, processes, and relationships, assemblage theory invites novel ways of understanding the role of experiential knowledge on reproductive planning.

CTLA-4 Checkpoint Inhibition Improves Sepsis Survival in Alcohol-Exposed Mice.

Chronic alcohol use increases morbidity and mortality in the setting of sepsis. Both chronic alcohol use and sepsis are characterized by immune dysregulation, including overexpression of T cell coinhibitory molecules. We sought to characterize the role of CTLA-4 during sepsis in the setting of chronic alcohol exposure using a murine model of chronic alcohol ingestion followed by cecal ligation and puncture. Results indicated that CTLA-4 expression is increased on CD4+ T cells isolated from alcohol-drinking septic mice as compared with either alcohol-drinking sham controls or water-drinking septic mice. Moreover, checkpoint inhibition of CTLA-4 improved sepsis survival in alcohol-drinking septic mice, but not water-drinking septic mice. Interrogation of the T cell compartments in these animals following pharmacologic CTLA-4 blockade, as well as following conditional Ctla4 deletion in CD4+ T cells, revealed that CTLA-4 deficiency promoted the activation and proliferation of effector regulatory T cells and the generation of conventional effector memory CD4+ T cells. These data highlight an important role for CTLA-4 in mediating mortality during sepsis in the setting of chronic alcohol exposure and may inform future approaches to develop targeted therapies for this patient population.

CTLA-4 antibody-drug conjugate reveals autologous destruction of B-lymphocytes associated with regulatory T cell impairment

Germline CTLA-4 deficiency causes severe autoimmune diseases characterized by dysregulation of Foxp3+ Tregs, hyper-activation of effector memory T cells, and variable forms autoimmune cytopenia including gradual loss of B cells. Cancer patients with severe immune-related adverse events (irAE) after receiving anti-CTLA-4/PD-1 combination immunotherapy also have markedly reduced peripheral B cells. The immunological basis for B cell loss remains unexplained. Here, we probe the decline of B cells in human CTLA-4 knock-in mice by using anti-human CTLA-4 antibody Ipilimumab conjugated to a drug payload emtansine (Anti-CTLA-4 ADC). The anti-CTLA-4 ADC-treated mice have T cell hyper-proliferation and their differentiation into effector cells which results in B cell depletion. B cell depletion is mediated by both CD4 and CD8 T cells and at least partially rescued by anti-TNF-alpha antibody. These data revealed an unexpected antagonism between T and B cells and the importance of regulatory T cells in preserving B cells.

CTLA-4 antibody-drug conjugate reveals autologous destruction of B-lymphocytes associated with regulatory T cell impairment.

Germline CTLA-4 deficiency causes severe autoimmune diseases characterized by dysregulation of Foxp3+ Tregs, hyper-activation of effector memory T cells, and variable forms autoimmune cytopenia including gradual loss of B cells. Cancer patients with severe immune-related adverse events (irAE) after receiving anti-CTLA-4/PD-1 combination immunotherapy also have markedly reduced peripheral B cells. The immunological basis for B cell loss remains unexplained. Here, we probe the decline of B cells in human CTLA-4 knock-in mice by using anti-human CTLA-4 antibody Ipilimumab conjugated to a drug payload emtansine (Anti-CTLA-4 ADC). The anti-CTLA-4 ADC-treated mice have T cell hyper-proliferation and their differentiation into effector cells which results in B cell depletion. B cell depletion is mediated by both CD4 and CD8 T cells and at least partially rescued by anti-TNF-alpha antibody. These data revealed an unexpected antagonism between T and B cells and the importance of regulatory T cells in preserving B cells.

Deletion of the inhibitory co-receptor CTLA-4 enhances and invigorates chimeric antigen receptor T cells

Chimeric antigen receptor (CAR) Tcell therapy targeting CD19 has achieved tremendous success treating Bcell malignancies; however, some patients fail to respond due to poor autologous Tcell fitness. To improve response rates, we investigated whether disruption of the co-inhibitory receptors CTLA4 or PD-1 could restore CART function. CRISPR-Cas9-mediated deletion of CTLA4 in preclinical models of leukemia and myeloma improved CAR Tcell proliferation and anti-tumor efficacy. Importantly, this effect was specific to CTLA4 and not seen upon deletion of CTLA4 and/or PDCD1 in CAR Tcells. Mechanistically, CTLA4 deficiency permitted unopposed CD28 signaling and maintenance of CAR expression on the Tcell surface under conditions of high antigen load. In clinical studies, deletion of CTLA4 rescued the function of Tcells from patients with leukemia that previously failed CAR Tcell treatment. Thus, selective deletion of CTLA4 reinvigorates dysfunctional chronic lymphocytic leukemia (CLL) patient Tcells, providing a strategy for increasing patient responses to CAR Tcell therapy.

Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity

Activated phosphoinositide-3-kinase δ syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking. This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS. Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs. The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS. APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients.

Molecular profile of patients with inborn errors of immunity from Nepal

Background and AimsInborn errors of immunity (IEIs) are increasingly being diagnosed in various regions of the world. There are significant challenges in the diagnosis and treatment of IEIs in resource-limited countries. With the availability of one immunologist and increasing awareness, IEIs are diagnosed with increasing frequency and accuracy in Nepal. IEIs are also being evaluated in children presenting with autoimmune manifestations. We describe the profile of patients diagnosed with IEIs in Nepal during 2020–2022. MethodsRecords of all patients with IEIs who were diagnosed and treated at our tertiary care center in Nepal from August 2020 to April 2022 were analysed. Lead author (DB) has examined and diagnosed all cases. IEIs were diagnosed based on the European Society for Immunodeficiencies (ESID) diagnostic criteria and genetic analysis. ResultsThirty-two patients with IEI (19 boys; 13 girls) and 801 children with autoimmune disorders were diagnosed during the study period. Genetic analysis was done on 18 patients. The diagnostic profile of the patients includes patients with chronic granulomatous disease, X-linked agammaglobulinemia, severe combined immunodeficiency, Job syndrome, selective IgA deficiency, specific antibody deficiency, Wiskott-Aldrich Syndrome, CTLA4 deficiency, IPEX syndrome, IFN-IL12 axis defect, hereditary angioedema, MonoMac syndrome, ARPC1B deficiency, leukocyte adhesion defect, PAPA syndrome, autoimmune lymphoproliferative syndrome, ADA2 deficiency, early-complement deficiency lupus, familial cold auto-inflammatory syndrome, A20 haploinsufficiency, and Blau syndrome. Some patients succumbed before the scope of diagnosis. HSCT is planned for 3 patients. ConclusionsOur is the first report of genetically proven IEIs in Nepal. Logistic constraints coupled with a lack of awareness of IEIs among laity and pediatrician accounted for a missed diagnosis, late diagnosis, and poor outcomes in resource-limited settings. Antimicrobial prophylaxis reduced the incidence of breakthrough infections. The lack of HSCT facilities precludes definitive treatment of many IEIs.

A step closer to understanding the predisposition to autoimmunity as well humoral defects in aging patients with 22q11.2 deletion syndrome

IntroductionOur previous work has shown that despite having a small thymus with a limited T cell repertoire, the majority of patients with 22q11.2 deletion syndrome have a normal T cell proliferation at young age. As these patients age, their T cell numbers normalize yet about 25% have recurrent sinopulmonary infections and autoimmune disease, suggesting that their Tcell compartment exhibits some dysregulation. Follicular helper T cells (Tfh) are crucial for humoral immunity (germinal center formation, affinity maturation, memory B cell formation), yet there has been emerging evidence showing that Tfh cells contribute to the pathogenesis of autoimmune disease such as SLE where Tfh correlate with titers of autoantibodies and the severity of end-organ involvement. Similarly, Tfh cells play a role in the of autoimmunity in diseases of immune dysregulation such as CTLA-4 deficiency and IPEX syndrome where abundant Tfh cells may facilitate breakdown of the peripheral tolerance of autoreactive B cells. Given the crucial role Tfh cells play humoral immunity and occasionally autoimmunity we sought to look at the percentage of Tfh cells in older patients with 22q11.2 deletion syndrome. MethodsWe compared the percentage of peripheral blood Tfh cells in 16 patients with 22q11.2 (age range 9–38 years) to age-matched healthy controls. T-tests were used to define significance. ResultsTfh cells in patients with 22q11.2 deletion syndrome were statistically significantly higher when compared to healthy controls, 19% and 8% respectively, Figure 1. DiscussionWe hypothesize that the observed increase in Tfh cells population in older 22q11.2 deletion patients is contributing to their autoimmune propensity. Our finding aligns with others who reported Tfh cells to play a role in the pathogenesis of autoimmunity seen in immune dysregulation syndromes. Further understanding the intrinsic characteristics of Tfh cells in these patients could be helpful in identifying the subset of patients at risk of antibody deficiency as well autoimmunity. [Display omitted]

A227 CTLA-4 DEFICIENCY PRESENTING AS CROHN DISEASE IN A TEENAGE BOY WITH MULTI-SYSTEM INVOLVEMENT : A CASE REPORT

Abstract Background Cytotoxic-T-lymphocyte-antigen-4 is a negative immune regulator. CTLA-4 deficiency can cause a complex immune dysregulation syndrome that may present as inflammatory bowel disease. Purpose Case Description: A 14-year-old male presented with several years of abdominal pain, diarrhea, short stature and poor weight gain. Endocolonoscopy diagnosed Crohn disease, with patchy chronic colitis, an ileal granuloma and active duodenitis with intraepithelial lymphocytosis and villous blunting. MRE showed multiple abnormal small bowel loops. Past history included appendicitis, immune thrombocytopenic purpura and an episode each of Aeromonas, Y enterocolitica and C difficile colitis. Family history was negative for consanguinity, autoimmune conditions or immune defects. The patient received sulfasalazine, exclusive enteral nutrition and then budesonide MMX with limited response. His pre-biologic workup identified bilateral pulmonary nodules, which were negative for infection or malignancy on further investigation. He began Adalimumab, and after 2 months had nearly normalized his fecal calprotectin to 90 ug/g. His history, together with chronic neutropenia and hypogammaglobulinemia (IgG 3.3 g/L, IgA 0.29g/L) led to a comprehensive immune and cytopenia panel, which revealed heterozygous pathogenic variants in the CTLA4 gene c.424G>C, p.(Gly142Arg), associated with CTLA-4 deficiency related immunodeficiency. Parental testing was negative, indicating a de novo mutation. The patient was subsequently admitted to hospital with severe headache and transient aphasia. Brain MRI found hyperintense foci concerning for CTLA-4 deficiency-associated CNS inflammation. He had papilledema and lumbar puncture found increased ICP. During this admission he developed Salmonella sepsis. Repeat chest CT found extensive worsening multifocal parenchymal lesions. Extensive investigations to exclude malignancy or infection were negative, and the lung findings were felt to be Granulomatous and Lymphocytic Interstitial Lung Disease. He had elevated soluble IL-2 receptor level (2884 U/ml) and elevated CD4+PD1+ T cells in peripheral blood. Adalimumab was stopped, and he received IVIg, then Diamox with resolution of headache, followed by pulse methylprednisolone. He has since been maintained on Abatacept (a soluble CTLA-4 analog that inhibits T-cell activation). Follow up soluble IL2 receptor level was normal. PJP prophylaxis was started, as well as prophylactic dosing of IVIg and regular screening for EBV and CMV. Method - Result(s) - Conclusion(s) Discussion: Our patient had CTLA-4 deficiency and immune dysregulation affecting multiple organs (CNS, lung, and intestinal inflammation, autoimmune neutropenia and previous ITP). Abatacept is the preferred steroid-sparing treatment of enteropathy in CTLA-4 deficiency. Soluble IL2 receptor level is an indicator of T cell activation used for treatment monitoring. This case illustrates the importance of considering immune defects even in older children presenting with apparent IBD. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared INTESTINAL DISORDERS

Inborn errors of immunity and immunodeficiencies: Antibody-mediated pathology and autoimmunity as a consequence of impaired immune reactions.

B-cell tolerance to self-antigen is an active process that requires the temporal and spatial integration of signals of defined intensity. In common variable immune deficiency disorders, CTLA-4 deficiency, autoimmune lymphoproliferative syndrome, or in collagen VII deficiency, genetic defects in molecules regulating development, activation, maturation, and ECM composition alter the generation of B cells, resulting in immunodeficiency. Paradoxically, at the same time, the defective immune processes favor autoantibody production and immunopathology through impaired establishment of tolerance. The development of systemic autoimmunity in the framework of defective BCR signaling is relatively unusual in genetic mouse models. In sharp contrast, such reduced signaling in humans is clearly linked to pathological autoimmunity. The molecular mechanisms by which tolerance is broken in these settings are only starting to be explored resulting in novel therapeutic interventions. For instance, in CTLA-4 deficiency, homeostasis can be restored by CTLA-4 Ig treatment. Following this example, the identification of the molecular targets causing the reduced signals and their restoration is a visionary way to reestablish tolerance and develop novel therapeutic avenues for immunopathologies.

Clinical Courses of IKAROS and CTLA4 Deficiencies: A Systematic Literature Review and Retrospective Longitudinal Study.

IKAROS and CTLA4 deficiencies are inborn errors of immunity and show similar clinical phenotypes, including hypogammaglobulinemia and autoimmune diseases (ADs). However, the differences in clinical features and pathogenesis of these are not fully understood. Therefore, we performed systematic literature reviews for IKAROS and CTLA4 deficiencies. The reviews suggested that patients with IKAROS deficiency develop AD earlier than hypogammaglobulinemia. However, no study assessed the detailed changes in clinical manifestations over time; this was likely due to the cross-sectional nature of the studies. Therefore, we conducted a retrospective longitudinal study on IKAROS and CTLA4 deficiencies in our cohort to evaluate the clinical course over time. In patients with IKAROS deficiency, AD and hypogammaglobulinemia often develop in that order, and AD often resolves before the onset of hypogammaglobulinemia; these observations were not found in patients with CTLA4 deficiency. Understanding this difference in the clinical course helps in the clinical management of both. Furthermore, our results suggest B- and T-cell-mediated ADs in patients with IKAROS and CTLA4 deficiencies, respectively.

Hematopoietic stem cell transplantation for Inborn Errors of Immunity

Hematopoietic stem cell transplantation for Inborn Errors of Immunity

Autoimmunity in Primary Immunodeficiency Disorders: An Updated Review on Pathogenic and Clinical Implications.

During the last years, studies investigating the intriguing association between immunodeficiency and autoimmunity led to the discovery of new monogenic disorders, the improvement in the knowledge of the pathogenesis of autoimmunity, and the introduction of targeted treatments. Autoimmunity is observed with particular frequency in patients with primary antibody deficiencies, such as common variable immunodeficiency (CVID) and selective IgA deficiency, but combined immunodeficiency disorders (CIDs) and disorders of innate immunity have also been associated with autoimmunity. Among CIDs, the highest incidence of autoimmunity is described in patients with autoimmune polyendocrine syndrome 1, LRBA, and CTLA-4 deficiency, and in patients with STAT-related disorders. The pathogenesis of autoimmunity in patients with immunodeficiency is far to be fully elucidated. However, altered germ center reactions, impaired central and peripheral lymphocyte negative selection, uncontrolled lymphocyte proliferation, ineffective cytoskeletal function, innate immune defects, and defective clearance of the infectious agents play an important role. In this paper, we review the main immunodeficiencies associated with autoimmunity, focusing on the pathogenic mechanisms responsible for autoimmunity in each condition and on the therapeutic strategies. Moreover, we provide a diagnostic algorithm for the diagnosis of PIDs in patients with autoimmunity.

Germline Mutations in CTLA4 and Spectrum of Bone Marrow Features Overlapping with Aplastic Anemia and Large Granular Lymphocyte Lymphocytosis

Introduction: CTLA4 haploinsufficiency due to germline heterozygous mutations in the cytotoxic T-lymphocyte antigen-4 gene (CTLA4) results in severe systemic immune dysregulation; infiltrative lymphocytic lesions of lungs (e.g. lymphocytic pneumonitis), GI tract (e.g.lymphocytic colitis), and CNS; and a spectrum of autoimmunity, immunodeficiency and peripheral blood cytopenias. We describe the hematologic, bone marrow (BM), and flow cytometry (FC) features of CTLA4 haploinsufficiency of a cohort of 14 patients, which show overlapping morphologic features with acquired aplastic anemia (acAA), and large granular lymphocyte lymphocytosis (LGL) in a subset of patients. We compared the findings to those in a separate cohort of 20 age matched patients diagnosed with acAA. There were significant differences between acAA and CTLA4 deficiency based on analysis of BM lymphocyte subsets and marrow lymphocyte infiltration patterns.Materials and Methods: Peripheral blood (PB), BM and FC analysis of patients with germline mutations in CTLA4, and acAA was performed along with review of clinical, molecular and laboratory data. Statistical comparisons were made using Mann Whitney test, with p < 0.05 for significance.Results: Median age at initial evaluation for patients with CTLA4 haploinsufficiency was 23.5 years (range 11-71 years), with a male-to-female ratio of 11:3. 11 out of 14 patients had cytopenias. Of those with cytopenias 2/11 had pancytopenia, 4/11 had bicytopenia and 5/11 had unilineage cytopenia. Hypogammaglobulinemia was common (13/14). In some cases cytopenias were recognized as autoimmune in etiology with immune thrombocytopenic purpura and autoimmune hemolytic anemia, among the most common hematologic manifestations. Three patients met criteria for a diagnosis of moderate AA, 1 for severe AA, and 1 for LGL. Overall bone marrow biopsies were hypocellular for age (10/14) with a subset (29% [4/14]) showing severe trilineage hypoplasia with ≤20% cellularity. Atypical interstitial CD8-positive T-cell infiltrates with prominent non-paratrabecular CD4-positive T-cell aggregates were evident by immunohistochemistry in most cases (10/14), accompanied by a near absence of B-cells. T-cell clonality was assessed by T-cell receptor (TCR) gamma PCR and showed abnormal oligoclonal T-cell populations in 3/8, and one case with a clonal T-cell receptor gene rearrangement. B-cell IgH PCR reactions were polyclonal. In all cases, cytogenetic studies were either negative or showed only minor abnormalities (i.e. loss of Y chromosome). Given the morphologic overlap of a subset of CTLA4 cases with acAA, we compared bone marrow flow cytometry analysis of 8 CTLA4 cases with 20 acAA cases. CTLA4 patients showed >5 fold reduction in the median percentage of B-cells in comparison to acAA (p=0.0005). While acAA cases demonstrated relative preservation the B-cell compartment with intact B-cell maturation sequence; in contrast CTLA4 cases showed abnormal B-cell maturation patterns in half of cases characterized by few detectable early B-cell precursors, and progressive loss of intermediate and mature forms. T-cell populations in CTLA4 showed inverted CD4:CD8 ratios with relatively increased CD57+ T-cells, and atypical dim expression of CD20 on T-cells. Morphologically, when the markedly hypocellular CTLA4 cases were compared to acAA on core biopsies, little difference in marrow cellularity was seen; however, the CTLA4 cases showed multiple large atypical T-cell aggregates and near total absence of B-cells, which was not seen in acAA; acAA cases showed scattered background T-cells and B-cells.Conclusions: CTLA-4 deficiency presents with cytopenias, autoimmunity, and immunodeficiency with a subset of patients that have features overlapping with bone marrow failure, specifically AA and LGL. Herein we demonstrate a combination of abnormal BM findings, previously unreported, comprising hypocellularity, CD8-positive interstitial T-cell infiltrates with atypical CD4-positive T-cell aggregates, marked B-cell lymphopenia, increased LGLs and abnormal T-cell clonality patterns by PCR. These features may help identify patients harboring CTLA4 mutations for early detection and optimal therapeutic management. DisclosuresYoung:Novartis/GSK to institute: Research Funding. Townsley:Novartis/GSK to institute: Research Funding.

The paradigm of hematological malignant versus non-malignant manifestations, driven by primary immunodeficiencies: a complex interplay.

Hematological malignancies (HM) developed on underlying primary immunodeficiencies (PID) are rare and of unusual features. Differentiating between malignant and non-malignant lymphoproliferation in cases of pediatric hematology and oncology and revealing their molecular predisposition demonstrate the complex interplay between PID and HM. We retrospectively studied a case series of seven pediatric patients, all with PID with manifestations raising suspicion for HM or hypereosinophilic syndrome (HES) or confirmed HM of lymphoid origin. Combined immunodeficiency (CID) without detection of a known mutated gene or with ataxia-telangiectasia (AT), STAT3 gain of function (GOF), DOCK8 deficiency, and CTLA4 deficiency were diagnosed in three, one, one, one, and one patient, respectively. Acute lymphoblastic leukemia and Hodgkin lymphoma followed by second primary Burkitt lymphoma were diagnosed in one patient with CID each, while lymphomatoid granulomatosis in one patient with AT. Lymphoproliferative disease occurred in STAT3 GOF, CTLA4 deficiency and CID, one patient each, and idiopathic HES in DOCK8 deficiency (median age at presentation of PID or any hematological manifestation: four years). Four patients underwent hematopoietic cell transplantation (HCT) for STAT3 GOF, DOCK8 deficiency and CID in one, one, and two cases, respectively (median age: 10years). At the last follow-up, all transplanted patients were alive. Reporting on patients' phenotype, genotype and course of disease shed light on the prevalence, characteristics, and pathophysiology of HM complicating PID. Discriminating the non-yet malignant lymphoproliferation from its malignant equivalent on the same pathophysiology background proved of additional value. Outcomes of PID after HCT, herein reported, are favorable.

Retrospective Analysis of Autoimmune Diseases and Immunologic Characteristics of the Adult Primary Immune Deficiency Cohort: 17 Years Experience of the Tertiary Referral Immunology Center in Turkey

ABSTRACT Objective: Primary immunodeficiencies (PIDs) consist of genetically heterogeneous disorders. The spectrum can include infectious diseases, malignancy, allergy, and autoimmunity. We aimed to analyze the frequency and variety of autoimmune diseases (ADs) in PIDs and describe their clinical and laboratory features. Materials and Methods: Ninety-two patients with PID followed by Ege University Medical Faculty between 2000 and 2017 were enrolled in this retrospective, cross-sectional study. All patients’ medical records were reviewed using the demographic information, type of PIDs and ADs, ADs-related autoantibodies, and basic and immunologic laboratory findings. ADs were diagnosed using clinical and complementary paraclinical findings by an immunologist and/or a subspecialist related to the affected organ or system. Results: We evaluated 50 male and 42 female PID patients with a mean age of 40.92 (18-86). Twenty-nine (32 %) patients (15 females/14 males) with a mean age of 43.8 (19-78) had ADs. In our study group, the most commonly detected type of PID with AD is common variable immune deficiency (CVID) (n=17); followed by combined immune deficiency (CID) (n=3), CTLA4 deficiency (n=2), selective IgA deficiency (sIgAD) (n=2), specific IgG subgroup deficiency (n=1), autoimmune polyglandular syndrome (APS) with hypogammaglobulinemia (n=1), dyskeratosis congenita (DC) (n=1), Osler-Rendu-Weber (ORW) syndrome with CVID-like PID (n=1), and cartilage-hair hypoplasia (CHH) (n=1). According to systematic assessments, ADs resulted in endocrinologic 14%, dermatologic 10.8%, rheumatologic 9.7%, gastroenterological 9.7%, hematological 8.6%, and neurologic disorders 1%. The frequency of ADs was higher in CVID cases than other types of PIDs (p &lt;0.05). Basic and immunologic laboratory findings of the PIDs with and without ADs were analyzed and compared; however, no statical significant difference was obtained between the groups. Conclusion: We have analyzed the frequency and variety of ADs in a adult PID cohort in Turkey. Patients presenting with multiple ADs should be screened for having an underlying PID. Keywords: Primary immune deficiency, autoimmunity, autoantibody, immunologic parameters, frequency

КЛИНИЧЕСКАЯ ХАРАКТЕРИСТИКА ГРУППЫ ПАЦИЕНТОВ С СИНДРОМОМ ГАПЛОНЕДОСТАТОЧНОСТИ CTLA4: ОПЫТ ОДНОГО ЦЕНТРА

CTLA4 deficiency is a primary immunodeficiency state (PIDS) caused by monoallelic mutations in the gene of the same name, and belongs to the group of immunodeficiencies with immune dysregulation. This work analyzes the results of 11 patients with CTLA4 mutations observed at the Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology from October 2012 to January 2021. In 10 of 11 patients had some manifestations of immune dysregulation, the most frequent were cytopenias (10/11), lymphoproliferation (9/11) and lung damage caused by the type of interstitial lymphocytic lungs disease (9/11). Almost all patients had such abnormal immune parameters as hypogammaglobulinemia or dysgammaglobulinemia, lymphopenia. Currently, there is no standardized treatment for these patients, however, targeted therapy with biologically modified CTLA4 is a promising approach to the treatment of autoimmune complications in patients with CTLA4 deficiency. The only curative treatment option for patients with PIDS is hematopoietic stem cell transplantation, but in order to make conclusions about the effectiveness and safety of this treatment, a long period of observation and large groups of patients are required.

Autoimmune Cytopenias in Nonmalignant Lymphoproliferative Disorders: Thinking Beyond ALPS(Autoimmune Lymphoproliferative Syndrome)

The ALPS Clinic at NIH has studied autoimmune lymphoproliferative disorders for over 30 years elucidating the genetic underpinnings and natural history of Autoimmune Lymphoproliferative Syndrome (ALPS) due to FAS gene defects (Blood 2014). Over the years, we continue to receive and work-up numerous referrals for diseases that masquerade like ALPS-FAS, presenting with multi-lineage cytopenias due to autoimmune peripheral destruction and splenic sequestration in the setting of non-malignant lymphoproliferation. In a review of 259 cases evaluated by our team, there were 150 ALPS-FAS, 54 Activated PI3K-delta Syndrome (APDS), 31 CTLA-4 Haploinsufficiency (CTLA4), 7 LRBA deficiency (LRBA), and 17 MAGT-1 deficiency (XMEN) patients. Non-malignant lymphadenopathy and splenomegaly occurred on average in 83% and 71% of all patients, respectively. Anemia, thrombocytopenia, and neutropenia were seen in 65%, 58%, and 46%, respectively. Thus, autoimmune cytopenias in the setting of non-malignant lymphoproliferation in themselves are not adequate to rule in or rule out a presumptive diagnosis of ALPS-FAS. Timely and accurate genetic diagnosis of ALPS-like conditions will improve the morbidity and mortality associated with these disease processes. Rapamycin, an m-TOR inhibitor provides salutary benefits for many of these conditions by restoring the TREG function and reversing immune-dysregulation. For example, in addition to lymphadenopathy and splenomegaly associated with an increased risk of malignant lymphoma like ALPS-FAS patients, APDS patients usually present with recurrent sinopulmonary and ear infections. Their serum IgM tends to be elevated with low IgG levels. Unlike for ALPS-FAS patients, a potential targeted treatment for APDS exists: Leniolisib, a targeted PI3Kinase p-110 delta inhibitor is currently undergoing clinical trials (Blood 2016). CTLA-4 is critical for T-cell activation and immune check-point regulation by tempering regulatory T cell function. Patients affected by CTLA4 and LRBA variants present with symptoms of lymphocytic infiltration of the bone marrow (often leading to hypoplastic anemia), gut (colitis, bowel obstruction), lungs (bronchiectasis, restrictive airway disease), and central nervous system (seizures and neurological deficits due to brain and spinal cord lesions). They also tend to have B cell lymphopenia, low IgG and IgM levels. CTLA4 and LRBA patients share pathophysiology as well as clinical phenotype because LRBA gene regulates intracellular lysosomal trafficking and recycling of CTLA-4 protein. Hence CTLA-4 haploinsufficiency or LRBA deficiency renders both patient types CTLA-4 deficient. This can be directly addressed with abatacept infusions, a CTLA-4 hybridized immunoglobulin given as a combination immunosuppressive therapy with rapamycin. Abatacept replaces the CTLA-4 molecule and reverses some of the immune dysregulation and thus morbidity associated with both CTLA4 and LRBA deficiency. Like APDS patients, XMEN patients are also prone to recurrent ear and sinopulmonary infection, but key differentiating features of this X-linked disorder are that only males are affected, these patients are unable to clear Epstein-Barr virus (EBV) once exposed, and they have a propensity to develop EBV-driven lymphomas. These patients also usually have a strong family history of multiple lymphomas in males. Even though a targeted treatment does not yet exist, steroid-sparing measures such as rituximab, rapamycin and mycophenolate mofetil are the first-line treatments often used in managing their refractory autoimmune cytopenias. Hence accurate early genetic diagnosis is key to accessing the appropriate treatment, thus decreasing the morbidity and mortality associated with these childhood onset ALPS-like rare inherited disorders (table). Table Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Rapamycin, Abatacept, Mycophenolate Mofetil.

Lymphocytic and collagenous colitis in children and adolescents: Comprehensive clinicopathologic analysis with long-term follow-up

Microscopic colitis (MC) is characterized by chronic watery diarrhea, endoscopically normal findings, and abnormal histology. While mostly encountered in adults, pediatric cases are rare and may show varying presentations. Our pathology data system was searched from 1984 to 2019 for patients ≤18 years of age with a lymphocytic colitis (LC) or collagenous colitis (CC) pattern of injury. Twenty-seven cases (23 LC and 4 CC) were retrieved. LC was more prevalent than CC (85% vs 15%, respectively) and affected slightly younger individuals (mean, 9.8 years versus 12.25 years). Immune dysregulation was documented in 11 (41%) patients. Most patients presented with watery diarrhea (n=26, 96%) and either abdominal pain (n=18, 67%), nausea/vomiting (n=5, 19%), flatulence (n=6, 22%), and/or weight loss (n=1, 4%). A subset of patients (n=10, 37%) demonstrated endoscopic abnormalities. Histologically, some patients with LC and CC displayed focal cryptitis or crypt abscess formation (n=7, 26%) and focally increased crypt apoptosis (n=9, 33%) in the absence of chronic injury. Clinical follow-up data were available for 23 (85%) patients with variable clinical responses recorded. Only 8 patients experienced complete symptom resolution. Twelve patients (11 LC and 1 CC) had subsequent biopsy material; of which, one developed histologic features of inflammatory bowel disease and another was found to have a CTLA-4 deficiency. Our study shows that pediatric patients with MC may have atypical clinical, histologic, and endoscopic findings and variable clinical responses. Underlying inflammatory and/or genetic conditions may be eventually unmasked, and genetic testing may be helpful in a small subset of patients.