Explore the vast range of titles available.

The phenotypic heterogeneity may be the result of variable penetrance and expressivity, epigenetic influences or epistasis caused by gene-gene interactions. Because of genetic and phenotypic heterogeneity, there has been understandable reluctance to routinely sequence CVID patients because of the low yield (25). Given the rapid progress in the understanding of these conditions in recent years, we believe there is now a strong case for routine diagnostic genetic testing of patients with a CVID phenotype (Table 1). Establishing the diagnosis Confirming the clinical diagnosis of a CVID-like disorder Identifying novel presentations of other CVID-like disorders eg as LOCID Identifying atypical presentations of other PIDs with hypogammaglobulinemia eg XLP Distinguishing genetic from acquired disorders eg drug-induced hypogammaglobulinemiaIdentifying digenic disordersTHA-Variability of IgG levels over time: some of these patients may have CVID-like disordersDifferences in diagnostic criteria for CVID: the presence of a CVID-like disorder will obviate the need to apply CVID diagnostic criteria.Identifying CVID-like disorders in patients who have already developed malignancyIdentifying CVID-like disorders in patients on SCIG/IVIG or immunosuppression Treatment Offering early SCIG/IVIG treatment for individuals carrying causative mutationsIdentifying specific treatment options eg abatacept for CTLA-4/LRBA deficiency Identifying patients who may benefit from gene based therapy in the future Prognosis Asymptomatic patients with monogenic defects have a high probability of symptomatic disease, leading to long-term SCIG/IVIG treatmentMay distinguish patients with THI, who may not recover till adulthood where some have impaired vaccine responses Pre-symptomatic testing Where presymptomatic diagnosis (at any age) is not possible with protein based tests eg patients with CVID-like disorders who are asymptomatic with normal immunoglobulins Diagnosis in infancy where conventional diagnostic tests are unreliable eg because of transplacentally acquired IgG levels Screening Cascade screening of at-risk relatives with or without symptoms after genetic counselingIdentifying mutations from tissue samples from deceased relativesIdentifying mutations from Guthrie cards from deceased relatives PID prevention Prenatal diagnosis with chorionic villus sampling (CVS) Pre-implantation genetic diagnosis (PGD) Research Characterizing the role of molecules in cellular function Assisting with the classification of primary immunodeficiency disorders Identification of new genetic defects with trio analysisInvestigating animal models of CVID-like disordersIdentifying epistasis caused by digenic (or oligogenic) disorders Most of the clinical scenarios are described in the text.

Although recurrent infections in Rubinstein–Taybi syndrome (RSTS) are common, and probably multifactorial, immunological abnormalities have not been extensively described with only isolated cases or small case series of immune deficiency and dysregulation having been reported. The objective of this study was to investigate primary immunodeficiency (PID) and immune dysregulation in an international cohort of patients with RSTS. All published cases of RSTS were identified. The corresponding authors and researchers involved in the diagnosis of inborn errors of immunity or genetic syndromes were contacted to obtain up-to-date clinical and immunological information. Ninety-seven RSTS patients were identified. For 45 patients, we retrieved data from the published reports while for 52 patients, a clinical update was provided. Recurrent or severe infections, autoimmune/autoinflammatory complications, and lymphoproliferation were observed in 72.1%, 12.3%, and 8.2% of patients. Syndromic immunodeficiency was diagnosed in 46.4% of individuals. Despite the broad heterogeneity of immunodeficiency disorders, antibody defects were observed in 11.3% of subjects. In particular, these patients presented hypogammaglobulinemia associated with low B cell counts and reduction of switched memory B cell numbers. Immunoglobulin replacement therapy, antibiotic prophylaxis, and immunosuppressive treatment were employed in 16.4%, 8.2%, and 9.8% of patients, respectively. Manifestations of immune dysfunctions, affecting mostly B cells, are more common than previously recognized in patients with RSTS. Full immunological assessment is warranted in these patients, who may require detailed investigation and specific supportive treatment.

Abstract Background Hypergammaglobulinemia poses a challenge for identifying and quantitating monoclonal proteins (M-protein). The Increased polyclonal immunoglobulin background can lead to imprecise estimation of the M-protein when quantitated by serum protein electrophoresis (SPEP). This is especially true using the perpendicular drop method of peak integration. Hypergammaglobulinemia also makes it difficult to detect small M-proteins on immunofixation electrophoresis. Overestimation of M-protein concentration can lead to unnecessary follow-ups while missing small M-proteins can mask the underlying diagnosis for patients. In this study, we retrospectively evaluated the prevalence and concentration of M-protein within polyclonal hypergamma backgrounds using immunocapture matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (MASS-FIX). Methods We retrospectively analyzed 47061 unique patients tested for SPEP and MASS-FIX in 2022 at Mayo Clinic. If a patient underwent multiple tests during this period, only the first result was included in the analysis. Polyclonal hypergammaglobulinemia was defined as a gamma fraction >1.7g/dL by SPEP. MASS-FIX was used to identify and isotype M-proteins. MASS-FIX was then combined with total immunoglobin quantitation (IgG, IgA or IgM) using nephelometry to quantify concentration of the M- protein using mathematical modeling (method currently under validation). Results Of the 47,061 unique patients, 24,796 were normal by SPEP (53%). M-spikes were present in 5,808 cases (12%). Hypogammaglobulinemia (gamma fraction < 0.5g/dL) in 2897 cases (6%). Small non-quantifiable M-proteins by SPEP were present in 8363 cases (18%). [JC2] There were 4222 hypergamma cases in the cohort (9%), without a quantitative M-spike on SPEP. Of these, 16.1% (680/4222) patients had an M-protein by MASS-FIX. When polyclonal hypergamma was the sole SPEP abnormality, 5.5% were MASS-FIX positive. However, when a small abnormality pattern was observed within the polyclonal hypergamma background on SPEP, 50% of patients were MASS-FIX positive. The most common isotype was IgG (27.2%), followed by IgM (10.2%), IgA (8.1%), and biclonal (3.7%), which is similar to overall isotype distribution in other backgrounds. Using quantitative MASS-FIX, we identified that 95% MASS-FIX positive small monoclonal proteins in polyclonal hypergamma are < 1 g/dL, which is the recommended limited of quantitation for M-protein using SPEP in setting of hypergammaglobulinemia. Conclusion Majority of polyclonal hypergammaglobulinemia cases (83.9%) do not have a monoclonal protein. MASS-FIX allows quantitation of small monoclonal proteins below the SPEP limit of quantitation, which can enhance our understanding of conditions which present with small M-proteins in a polyclonal hypergammaglobulinemia background. Small visual abnormalities within polyclonal hypergamma background on SPEP should be followed-up with immunofixation or MASS-FIX to confirm the presence or absence of M- proteins.

Deficiency of ADA2 (DADA2) is the first molecularly described monogenic vasculitis syndrome. DADA2 is caused by biallelic hypomorphic mutations in the ADA2 gene that encodes the adenosine deaminase 2 (ADA2) protein. Over 60 disease-associated mutations have been identified in all domains of ADA2 affecting the catalytic activity, protein dimerization, and secretion. Vasculopathy ranging from livedo reticularis to polyarteritis nodosa (PAN) and life-threatening ischemic and/or hemorrhagic stroke dominate the clinical features of DADA2. Vasculitis and inflammation can affect many organs, explaining the intestinal, hepatological, and renal manifestations. DADA2 should be primarily considered in patients with early-onset fevers, rashes, and strokes even in the absence of positive family history. Hematological manifestations include most commonly hypogammaglobulinemia, although pure red cell aplasia (PRCA), immune thrombocytopenia, and neutropenia have been increasingly reported. Thus, DADA2 may unify a variety of syndromes previously not thought to be related. The first-line treatment consists of TNF-inhibitors and is effective in controlling inflammation and in preserving vascular integrity. Hematopoietic stem cell transplantation (HSCT) has been successful in a group of patients presenting with hematological manifestations. ADA2 is highly expressed in myeloid cells and plays a role in the differentiation of macrophages; however, its function is still largely undetermined. Deficiency of ADA2 has been linked to an imbalance in differentiation of monocytes towards proinflammatory M1 macrophages. Future research on the function of ADA2 and on the pathophysiology of DADA2 will improve our understanding of the condition and promote early diagnosis and targeted treatment.

CD19-targeted chimeric antigen receptor (CAR) T-cell becomes a breakthrough therapy providing excellent remission rates and durable disease control for patients with relapsed/refractory (R/R) hematologic malignancies. However, CAR T-cells have several potential side effects including cytokine release syndrome, neurotoxicities, cytopenia, and hypogammaglobulinemia. Infection has been increasingly recognized as a complication of CAR T-cell therapy. Several factors predispose CAR T-cell recipients to infection. Fortunately, although studies show a high incidence of infection post-CAR T-cells, most infections are manageable. In contrast to patients who undergo hematopoietic stem cell transplant, less is known about post-CAR T-cell immune reconstitution. Therefore, evidence regarding antimicrobial prophylaxis and vaccination strategies in these patients is more limited. As CAR T-cell therapy becomes the standard treatment for R/R B lymphoid malignancies, we should expect a larger impact of infections in these patients and the need for increased clinical attention. Studies exploring infection and immune reconstitution after CAR T-cell therapy are clinically relevant and will provide us with a better understanding of the dynamics of immune function after CAR T-cell therapy including insights into appropriate strategies for prophylaxis and treatment of infections in these patients. In this review, we describe infections in recipients of CAR T-cells, and discuss risk factors and potential mitigation strategies.

The addition of rituximab to standard combination chemotherapy in children with high-grade (mainly Burkitt’s) lymphoma improved 3-year event-free survival (94% vs. 82%). The incidence of myelotoxic effects was somewhat higher, without a higher incidence of death from toxic effects; the incidence of hypogammaglobulinemia was higher.

Abstract Introduction/Objective Serum protein electrophoresis (SPEP) is the backbone laboratory test for the detection of abnormal monoclonal proteins. However, IFE is a sensitive assay that can sometimes detect monoclonal proteins even when the corresponding SPEP is negative. The fact that IFE is more sensitive than SPEP combined with the need to avoid overutilization of IFE has led to published algorithms for guidance. Hypogammaglobulinemia in a new patient has been recognized in these algorithms as a reason to reflex to IFE when SPEP is negative, though studies on veteran patients are sparse. Therefore, this QA study of the percentage of positive IFEs in negative new SPEP veteran patients with hypogammaglobulinemia was undertaken to ensure reflex IFEs would still be indicated. Methods As part of a quality assurance/quality improvement project, a retrospective Vista/Fileman search of all SPEPs with IFE performed from January 2017 to February 2019 was undertaken to identify cases of SPEPs showing hypogammaglobulinemia (<0.7 g/dL). Diagnostic comments were then analyzed to identify cases of hypogammaglobulinemia along with the M-spike (<0.1 g/dL) to identify negative SPEPs. Only those cases that were consistent with first time hypogammaglobulinemia without an obvious M-spike were included and tabulated for calculations. Any result that was not negative for a monoclonal band was considered as positive. Results There were a total of 194 specimens that met the criteria of SPEP with hypogammaglobulinemia and standard comments consistent with first time analysis and without an obvious M-spike on SPEP. Out of these 194 specimens, 45 had a positive result, either as a monoclonal band comigrating with the beta protein peak or as a very faint gamma or beta monoclonal band. This represented approximately 23% of the specimens, about double the literature published rate for the non-veteran population. Conclusion The performance of IFE on new hypogammaglobulinemia veteran patients appears to be indicated like previously published algorithms and is supported by the fact that about double (23%), compared to the non-veteran population, had positive IFEs despite negative SPEPs. IFE is a helpful tool for new hypogammaglobulinemia patients for the detection of monoclonal proteins despite negative SPEPs.

A patient with refractory CLL had delayed development of the rapid tumor lysis syndrome and remission after an infusion of T cells engineered to express an antigen receptor capable of recognizing B cells (CD19) coupled to two signaling molecules. With the use of gene-transfer techniques, T cells can be genetically modified to stably express antibodies on their surface, conferring new antigen specificity. Chimeric antigen receptors combine an antigen-recognition domain of a specific antibody with an intracellular domain of the CD3-zeta chain or FcγRI protein into a single chimeric protein. 1 , 2 Although chimeric antigen receptors can trigger T-cell activation in a manner similar to that of endogenous T-cell receptors, a major impediment to the clinical application of this technique to date has been limited in vivo expansion of chimeric antigen receptor T cells and disappointing clinical activity. 3 , 4 Chimeric antigen . . .