New primary immunodeficiencies 2023 update.

PURPOSE OF REVIEW: Primary immunodeficiency diseases (PIDs), also called inborn errors of immunity (IEI), are genetic disorders characterized by increased susceptibility to infection and/or aberrant regulation of immunological pathways. This review summarizes and highlights the new IEI disorders in the International Union of Immunological Societies (IUIS) 2022 report and current trends among new PIDs. RECENT FINDINGS: Since the 2019 IUIS report and the 2021 IUIS interim update, the IUIS IEI classification now includes 485 validated IEIs. Increasing utilization of genetic testing and advances in the strategic evaluation of genetic variants has continued to drive the identification of, not only novel IEI disorders, but additional genetic etiologies for known IEI disorders and phenotypes. SUMMARY: The recognition of new IEIs continues to advance at a rapid pace, which is due in part to increased performance and application of genetic modalities as well as expansion of the underlying science that is applied to convincingly establish causality. These disorders, as a whole, continue to emphasize the specificity of immunity, complexity of immune mechanisms, and the fine balance that defines immune homeostasis.

Clinical Practice Guidelines for the Immunological Management of Chromosome 22q11.2 Deletion Syndrome and Other Defects in Thymic Development.

Current practices vary widely regarding the immunological work-up and management of patients affected with defects in thymic development (DTD), which include chromosome 22q11.2 microdeletion syndrome (22q11.2del) and other causes of DiGeorge syndrome (DGS) and coloboma, heart defect, atresia choanae, retardation of growth and development, genital hypoplasia, ear anomalies/deafness (CHARGE) syndrome. Practice variations affect the initial and subsequent assessment of immune function, the terminology used to describe the condition and immune status, the accepted criteria for recommending live vaccines, and how often follow-up is needed based on the degree of immune compromise. The lack of consensus and widely varying practices highlight the need to establish updated immunological clinical practice guidelines. These guideline recommendations provide a comprehensive review for immunologists and other clinicians who manage immune aspects of this group of disorders.

New primary immunodeficiencies 2021 context and future.

PURPOSE OF REVIEW: Primary immunodeficiency diseases (PIDs), also called inborn errors of immunity (IEI), are genetic disorders classically characterized by an increased susceptibility to infection and/or disruption in the regulation of an immunologic pathway. This review summarizes and highlights the new IEI disorders in the IUIS 2019 report and 2020 interim report and discusses the directions for the future management of PIDs. RECENT FINDINGS: Since 2017, the International Union of Immunologic Societies (IUIS) IEI committee has updated the IUIS classification of IEIs with 88 new gene defects and 75 new immune disorders. The increased utilization of genetic testing and advances in the strategic evaluation of genetic variants have identified, not only novel IEI disorders, but additional genetic causes for known IEI disorders. Investigation of potential immune susceptibilities during the ongoing COVID-19 pandemic suggests that defects in Type I interferon signalling may underlie more severe disease. SUMMARY: The rapid discovery of new IEIs reflects the growing trend of applying genetic testing modalities as part of medical diagnosis and management.In turn, elucidating the pathophysiology of these novel IEIs have enhanced our understanding of how genetic mutations can modulate the immune system and their consequential effect on human health and disease.

New primary immunodeficiency diseases: context and future.

PURPOSE OF REVIEW: Primary immunodeficiency diseases (PIDs) are genetic disorders classically characterized by impaired host defense and an increased susceptibility to infections. It is now appreciated that these conditions broadly include variations in the genetic code that cause dysregulated immune function. This review highlights the newly defined PIDs in the 2017 International Union of Immunologic Societies (IUIS) report, current approaches to diagnosing PIDs, and the implications for the future management of PIDs. RECENT FINDINGS: With the advances in and increased commercial availability of genetic testing and the adoption of the TREC assay into the US Newborn Screening program, the number of identified PIDs has exponentially risen in the past few decades, reaching over 350 disorders. The IUIS Inborn Errors of Immunity committee acknowledged at least 50 new disorders between 2015 and 2017. Furthermore, given the greater recognition of disorders with primarily immune dysregulation, the committee proposed a more inclusive term of 'inborn errors of immunity' to encompass primary immunodeficiencies and immune dysregulation disorders. SUMMARY: This latest IUIS report underscores the rapid expansion in the PID field with technologic advancements in immunogenetics and clinical screening discovering new genetic diseases, and therefore, paving the way to novel therapeutics and precision medicine.

Considerations in the Diagnosis of Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency that is caused by defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. The disease presents in most patients initially with infection, especially of the lymph nodes, lung, liver, bone, and skin. Patients with CGD are susceptible to a narrow spectrum of pathogens, and Staphylococcus aureus, Burkholderia cepacia complex, Serratia marcescens, Nocardia species, and Aspergillus species are the most common organisms implicated in North America. Granuloma formation, most frequently in the gastrointestinal and genitourinary systems, is a common complication of CGD and can be seen even before diagnosis. An increased incidence of autoimmune disease has also been described in patients with CGD and X-linked female carriers. In patients who present with signs and symptoms consistent with CGD, a flow cytometric dihydrorhodamine neutrophil respiratory burst assay is a quick and cost-effective way to evaluate NADPH oxidase function. The purpose of this review is to highlight considerations for and challenges in the diagnosis of CGD.

It's not just the food you eat: Environmental factors in the development of food allergies.

The dramatic rise in the prevalence of food allergy and food allergy-associated anaphylaxis in the past few decades has fueled investigative interest into understanding this puzzling trend. Here, we review the question as to whether important external environmental determinants beyond dietary habits and exposure to food allergens are involved. This review will summarize our current understanding of these environment determinants, derived from the latest experimental and epidemiological research. Specifically, we will review the role of exposures that affect skin barrier function, development of a diverse microbiome, and food processing. Additional exposures of concern are insufficient sunlight, endocrine disrupting chemicals and pesticides, and use of specific pharmaceutical agents that may drive or modify the risk for food allergy. Despite limitations in the quantity and quality of research to date, many new epidemiological associations and experimental data in support of this paradigm have emerged.

The Epidemiology of Anaphylaxis.

Anaphylaxis is a dramatic expression of systemic allergy. The lifetime prevalence of anaphylaxis is currently estimated at 0.05-2 % in the USA and ~3 % in Europe. Several population-specific studies have noted a rise in the incidence, particularly in the hospitalizations and ER visits due to anaphylaxis. The variable signs and symptoms that constitute the diagnostic criteria for anaphylaxis, the differences in diagnostic algorithms, and the limitations in the current coding systems have made summarizing epidemiologic data and comparing study results challenging. Nevertheless, across all studies, the most common triggers continue to be medications, food, and venom. Various risk factors for more severe reactions generally include older age, history of asthma, and having more comorbid diseases. Interesting seasonal, geographic, and latitude differences have been observed in anaphylaxis prevalence and incidence rates, suggesting a possible role of vitamin D and sun exposure in modifying anaphylaxis risk. While the incidence and prevalence of anaphylaxis appear to be increasing in certain populations, the overall fatality rate remains relatively low.

TLR-mediated B cell defects and IFN-α in common variable immunodeficiency.

Common variable immune deficiency (CVID) B cells have impaired responses to TLR7 and TLR9 agonists including poor cell proliferation, loss of cytokine production, and failure to produce IgG or IgA. We show that TLR7- or 9-activated B cells from CVID subjects with >0.5% peripheral isotype-switched CD27(+) B cells (group 2) have increased mature Cγ1 and Cγ2 heavy-chain mRNA transcripts compared to subjects who have <0.5% isotype-switched cells (group 1). While TLR-stimulated CVID plasmacytoid dendritic cells for all subjects had impaired IFN-α production, TLR7 or TLR9 stimulation in the presence IFN-α normalized isotype-switched CD27(+) B cells, enhanced activation-induced cytidine deaminase mRNA, and significantly improved IgG production only for group 2 subjects. IFN-α also upregulated TLR7 and TLR9 mRNA expression comparable to normal levels in B cells of group 2 subjects, indicating that the loss of IFN-α could be a significant component of the B-cell defect for these subjects.

Toll-like receptor 4-, 7-, and 8-activated myeloid cells from patients with X-linked agammaglobulinemia produce enhanced inflammatory cytokines.

BACKGROUND: Bruton tyrosine kinase (BTK) is a component of signaling pathways downstream from Toll-like receptors (TLRs) 2, 4, 7, 8, and 9. Previous work in BTK-deficient mice, cell lines, and cultured cells from patients with X-linked agammaglobulinemia (XLA) suggested defective TLR-driven cytokine production. OBJECTIVE: We sought to compare TLR-4-, TLR-7-, and TLR-8-induced cytokine production of primary cells from patients with XLA with that seen in control cells. METHODS: PBMCs from patients with XLA, freshly isolated plasmacytoid dendritic cells, monocytes, and monocytoid dendritic cells were activated with TLR-4, TLR-7, and TLR-8 agonists. Signaling intermediates and intracellular and secreted cytokine levels were compared with those seen in control cells. RESULTS: Although TLR-4, TLR-7, and TLR-8 activation of nuclear factor κB and mitogen-activated protein kinase pathways in cells from patients with XLA and control cells were comparable, TLR-activated freshly isolated monocytes and monocytoid dendritic cells from patients with XLA produced significantly more TNF-α, IL-6, and IL-10 than control cells. TLR-7/8-activated plasmacytoid dendritic cells produced normal amounts of IFN-α. In murine models BTK regulates the degradation of Toll-IL-1 receptor domain-containing adaptor protein, terminating TLR-4-induced cytokine production. Although this might explain the heightened TLR-4-driven cytokine production we observed, Toll-IL-1 receptor domain-containing adaptor protein degradation is intact in cells from patients with XLA, excluding this explanation. CONCLUSION: In contrast to previous studies with BTK-deficient mice, cell lines, and cultured cells from patients with XLA suggesting impaired TLR-driven cytokine production, these data suggest that BTK inhibits TLR-induced cytokine production in primary human cells.

Toll-like receptor function in primary B cell defects.

Primary immunodeficiency diseases include more than 150 different genetic defects, classified on the basis of the mutations or physiological defects involved. The first immune defects to be well recognized were those of adaptive immunity affecting B cell function and resulting in hypogammaglobulinemia and defects of specific antibody production; more recently, novel defects of innate immunity have been described, some involving Toll-like receptors (TLRs) and their signaling pathways. Furthermore, it is increasingly evident that the innate and adaptive pathways intersect and reinforce each other. B cells express a number of TLRs, which when activated lead to cell activation, up-regulation of co-stimulatory molecules, secretion of cytokines, up-regulation of recombination enzymes, isotype switch and immune globulin production. TLR activation of antigen presenting cells leads to heightened cytokine production, providing additional stimuli for B cell development and maturation. Recent studies have demonstrated that patients with common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA) have altered TLR responsiveness. We review TLR defects in these disorders of B cell development, and discuss how B cell gene defects may modulate TLR signaling.

High levels of Crohn's disease-associated anti-microbial antibodies are present and independent of colitis in chronic granulomatous disease.

Chronic granulomatous disease (CGD) and inflammatory bowel disease (IBD) have overlapping gastrointestinal manifestations. Serum antibodies to intestinal microbial antigens in IBD are thought to reflect a loss of tolerance in the setting of genetically encoded innate immune defects. CGD subjects studied here, with or without colitis, had considerably higher levels of ASCA IgA, ASCA IgG, anti-OmpC, anti-I2, and anti-CBir1, but absent to low pANCA, compared to IBD-predictive cutoffs. Higher antibody levels were not associated with a history of colitis. Except for higher ASCA IgG in subjects <18 years, antibody levels were not age-dependent. In comparison, 7 HIES subjects expressed negative to low antibody levels to all of these antigens; none had colitis. Our results suggest that markedly elevated levels of antimicrobial antibodies in CGD do not correlate with a history of colitis but may reflect a specific defect in innate immunity in the face of chronic antigenic stimulation.

Toll-like receptor 7 and 9 defects in common variable immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia, reduced numbers of peripheral blood isotype-switched memory B cells, and loss of plasma cells. OBJECTIVE: Because Toll-like receptor (TLR) activation of B cells can initiate and potentially sustain normal B cell functions, we examined functional outcomes of TLR7 and TLR9 signaling in CVID B cells. METHODS: TLR7-mediated, TLR7/8-mediated, and TLR9-mediated cell proliferation, isotype switch, and immunoglobulin production by control and CVID B cells or isolated naive and memory B cell subsets were examined. We quantitated TNF-alpha, IL-6, and IL-12 production in response to TLR1-9 ligands and measured IFN-alpha production by TLR7-stimulated PBMCs and isolated plasmacytoid dendritic cells (pDCs). IFN-beta mRNA expression by TLR3-stimulated fibroblasts was assessed. RESULTS: Unlike CD27(+) B cells of controls, TLR7-activated, TLR7/8-activated, or TLR9-activated CVID B cells or isolated CD27(+) B cells did not proliferate, upregulate CD27, or shed surface IgD. TLR-stimulated CVID B cells failed to upregulate activation-induced cytosine deaminase mRNA or produce IgG and IgA. TLR7-stimulated PBMCs and pDCs produced little or no IFN-alpha. Reconstituting IFN-alpha in TLR7-stimulated CVID B-cell cultures facilitated proliferation, CD27 upregulation, and isotype switch. These TLR defects are restricted because CVID PBMCs stimulated with TLR ligands produced normal amounts of TNF-alpha, IL-6, and IL-12; TLR3-mediated expression of IFN-beta by CVID fibroblasts was normal. CONCLUSION: Defective TLR7 and TLR9 signaling in CVID B cells and pDCs, coupled with deficient IFN-alpha, impairs CVID B cell functions and prevents TLR-mediated augmentation of humoral immunity in vivo.

Development of a food allergy education resource for primary care physicians.

BACKGROUND: Food allergy is estimated to affect 3-4% of adults in the US, but there are limited educational resources for primary care physicians. The goal of this study was to develop and pilot a food allergy educational resource based upon a needs survey of non-allergist healthcare providers. METHODS: A survey was undertaken to identify educational needs and preferences for providers, with a focus on physicians caring for adults and teenagers, including emergency medicine providers. The results of the survey were used to develop a teaching program that was subsequently piloted on primary care and emergency medicine physicians. Knowledge base tests and satisfaction surveys were administered to determine the effectiveness of the educational program. RESULTS: Eighty-two physicians (response rate, 65%) completed the needs assessment survey. Areas of deficiency and educational needs identified included: identification of potentially life-threatening food allergies, food allergy diagnosis, and education of patients about treatment (food avoidance and epinephrine use). Small group, on-site training was the most requested mode of education. A slide set and narrative were developed to address the identified needs. Twenty-six separately enrolled participants were administered the teaching set. Pre-post knowledge base scores increased from a mean of 38% correct to 64% correct (p < 0.001). Ability to correctly demonstrate the use of epinephrine self injectors increased significantly. Nearly all participants (>95%) indicated that the teaching module increased their comfort with recognition and management of food allergy. CONCLUSION: Our pilot food allergy program, developed based upon needs assessments, showed strong participant satisfaction and educational value.

Memory B cells in common variable immunodeficiency: clinical associations and sex differences.

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired antibody responses, recurrent infections, inflammatory, autoimmune and malignancy-related conditions. We evaluated the relationship between memory B cell phenotype, sex, age at diagnosis, immunologic and clinical conditions in 105 CVID subjects from one medical center. Reduced numbers of switched memory B cells (cutoff