The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency.

Mice carrying the recessive locus for peripheral T cell deficiency (Ptcd) have a block in thymic egress, but the mechanism responsible is undefined. Here we found that Ptcd T cells had an intrinsic migration defect, impaired lymphoid tissue trafficking and irregularly shaped protrusions. Characterization of the Ptcd locus showed a point substitution of lysine for glutamic acid at position 26 in the actin regulator coronin 1A that enhanced its inhibition of the actin regulator Arp2/3 and resulted in its mislocalization from the leading edge of migrating T cells. The discovery of another coronin 1A mutant during an N-ethyl-N-nitrosourea-mutagenesis screen for T cell-lymphopenic mice prompted us to evaluate a T cell-deficient, B cell-sufficient and natural killer cell-sufficient patient with severe combined immunodeficiency, whom we found had mutations in both CORO1A alleles. Our findings establish a function for coronin 1A in T cell egress, identify a surface of coronin involved in Arp2/3 regulation and demonstrate that actin regulation is a biological process defective in human and mouse severe combined immunodeficiency.

Severe SOPH syndrome due to a novel NBAS mutation in a 27-year-old woman-Review of this pleiotropic, autosomal recessive disorder: Mystery solved after two decades.

Autosomal recessive SOPH syndrome was first described in the Yakuts population of Asia by Maksimova et al. in 2010. It arises from biallelic pathogenic variants in the NBAS gene and is characterized by severe postnatal growth retardation, senile facial appearance, small hands and feet, optic atrophy with loss of visual acuity and color vision, and normal intelligence (OMIM #614800). The presence of Pelger-Hüet anomaly in this disorder led to its name as an acronym for Short stature, Optic nerve atrophy, and Pelger-Hüet anomaly. Recent publications have further contributed to the characterization of this syndrome through additional phenotype-genotype correlations. We review the clinical features described in these publications and report on a 27-year-old woman with dwarfism with osteolysis and multiple skeletal problems, minor anomalies, immunodeficiency, diabetes mellitus, and multiple secondary medical problems. Her condition was considered an unknown autosomal recessive disorder for many years until exome sequencing provided the diagnosis by revealing a founder disease-causing variant that was compound heterozygous with a novel pathogenic variant in NBAS. Based on the major clinical features of this individual and others reported earlier, a revision of the acronym is warranted to facilitate clinical recognition.

Prescribing Immunoglobulin Replacement Therapy for Patients with Non-classical and Secondary Antibody Deficiency: an Analysis of the Practice of Clinical Immunologists in the UK and Republic of Ireland.

BACKGROUND: Immunologists are increasingly being asked to assess patients with non-classical and secondary antibody deficiency to determine their potential need for immunoglobulin replacement therapy (IGRT). Immunoglobulin is a limited, expensive resource and no clear guidance exists for this broad patient group. The purpose of this survey is to establish what factors influence the decision to commence IGRT in adult patients, when diagnostic criteria for primary antibody deficiency are not fulfilled. METHODS: Under the auspices of the United Kingdom Primary Immunodeficiency Network (UKPIN), a study group was established which circulated an online questionnaire to the consultant body across the UK and Ireland. Results provided a snapshot of the current clinical practice of 71% of consultant immunologists, from 30 centers. RESULTS: In order of importance, factors which influence the decision to commence IGRT include number of hospital admissions with infection, serum IgG level, bronchiectasis, radiologically proven pneumonia, number of positive sputum cultures, number of antibiotic courses, and results of immunization studies. The commonest test vaccine used was Pneumovax 23 with measurement of serotype-specific responses at 4 weeks, with a threshold of 0.35 µg/ml in 2/3 of serotypes measured. Eighty-six percent of patients are treated with a trial of prophylactic antibiotics prior to consideration of IGRT. Efficacy of IGRT trial is assessed at between 6 and 12 months. CONCLUSIONS: There was consistency in clinical practice using a combination of clinical history, evidence of infections, and vaccination testing for diagnosis. However, there was some variation in the implementation of this practice, particularly in vaccine choice and assessment of response to vaccination.

Overview of antibody-mediated immunity to S. pneumoniae: pneumococcal infections, pneumococcal immunity assessment, and recommendations for IG product evaluation.

Streptococcus pneumoniae (S. pneumoniae) strains colonize the nasopharynx and can cause mucosal infections in the upper airway and middle ear, pneumonias, and invasive infections like bacteremia, sepsis, and meningitis. Over 90 serotypes, defined by the structure of their capsular polysaccharides, are known. Twenty-three of these serotypes cause most infections and several of these serotypes can develop antibiotic resistance. Susceptibility factors that increase the susceptibility to S. pneumoniae mucosal and invasive infections include all forms of primary and secondary antibody deficiencies. Many patients affected by one of these deficiencies benefit from the regular administration of human gamma globulin (IgG) preparations. Donors of plasma units used to prepare human IgG have varying concentrations of IgG antibodies against relevant S. pneumoniae serotypes. These antibodies are developed in response to colonization and common subclinical infections and by routine vaccination with S. pneumoniae polysaccharide vaccines. The presence of an adequate concentration of these protective antibodies against all prevalent serotypes needs to be determined to assure the effectiveness of human IgG. All presently available methods to assess IgG antibodies against S. pneumoniae capsular polysaccharides have advantages and pitfalls that are analyzed in this review. In vitro testing does not provide a complete or necessarily accurate measurement of the effectiveness of antibodies in vivo. For regulatory purposes, caution needs to be used in the interpretation of currently available assays that measure pneumococcal antibody levels. Monitoring S. pneumoniae infections in patients treated with IgG and tracing information about IgG lots used to treat these patients should be encouraged.

Practice parameter for the diagnosis and management of primary immunodeficiency.

The American Academy of Allergy, Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma & Immunology (ACAAI) have jointly accepted responsibility for establishing the "Practice parameter for the diagnosis and management of primary immunodeficiency." This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion.

Modulatory role of intravenous gammaglobulin (IgIV) on the in vitro antibody response to a pneumococcal polysaccharide antigen.

INTRODUCTION: Clinical observations in patients with specific antibody deficiency treated for periods of time with IgG infusion have suggested that IgG may have a positive immunoregulatory effect on the production of specific antibodies against pneumococcal polysaccharides. We developed an in vitro model to test the effect of an IgIV preparation on the antibody production in response to a pneumococcal polysaccharide serotype and on the antibody and cytokine production in response to both a protein antigen and a pneumococcal polysaccharide antigen. METHODS: We studied 37 consecutive patients referred to our clinics for evaluation of their recurrent respiratory infections. Subjects were divided into two groups: 22 patients without SAD and 15 patients with SAD. PBMCs were left unstimulated or were stimulated with tetanus toxoid or pneumococcal polysaccharide serotype 19, in the presence of human albumin or IgIV. IgG anti-Pn-19 antibody, IL-4 and IFN-γ concentrations in culture supernatants were determined by ELISA. RESULTS: An increase in IgG anti-Pn-19 antibodies, associated with an increase in IFN-γ and a decrease in IL-4 production was observed in cultures stimulated with pneumococcal polysaccharide in the presence of IgIV when patients were analyzed together. The enhancing effect of IgIV was more significant for both IgG anti-Pn19 antibodies and IFN-γ in patients without SAD. In contrast, IgIV caused a significant decrease in IL-4 secretion in patients with SAD, which was associated with an increase in IgG anti-Pn19 antibodies in 3 of 7 of these patients. CONCLUSIONS: These results suggest that IgIV has some immunomodulatory effect on the in vitro production of IgG anti-Pn19 antibodies and cytokine production in cell cultures stimulated with Pn-19 antigen and that this modulation may be associated with a Th1/Th2 regulatory mechanism. Further studies at a cellular and molecular level are in progress to examine if the differences in the in vitro modulatory response to IgIV in these two groups of patients may point to a functional defect in patients with SAD.

Attending to warning signs of primary immunodeficiency diseases across the range of clinical practice.

PURPOSE: Patients with primary immunodeficiency diseases (PIDD) may present with recurrent infections affecting different organs, organ-specific inflammation/autoimmunity, and also increased cancer risk, particularly hematopoietic malignancies. The diversity of PIDD and the wide age range over which these clinical occurrences become apparent often make the identification of patients difficult for physicians other than immunologists. The aim of this report is to develop a tool for educative programs targeted to specialists and applied by clinical immunologists. METHODS: Considering the data from national surveys and clinical reports of experiences with specific PIDD patients, an evidence-based list of symptoms, signs, and corresponding laboratory tests were elaborated to help physicians other than immunologists look for PIDD. RESULTS: Tables including main clinical manifestations, restricted immunological evaluation, and possible related diagnosis were organized for general practitioners and 5 specialties. Tables include information on specific warning signs of PIDD for pulmonologists, gastroenterologists, dermatologists, hematologists, and infectious disease specialists. CONCLUSIONS: This report provides clinical immunologists with an instrument they can use to introduce specialists in other areas of medicine to the warning signs of PIDD and increase early diagnosis. Educational programs should be developed attending the needs of each specialty.

Recurrent respiratory infections, specific antibody deficiencies, and memory B cells.

OBJECTIVES: To investigate the immunological phenotypes detected in children with recurrent upper and lower respiratory infections that have normal total immunoglobulin concentrations. METHODS: A cohort of over 60 children with recurrent respiration infections was evaluated for specific antibody deficiencies (SAD) and for memory B-cell abnormalities. A control group of children without recurrent infections was also evaluated. Evaluation included a detailed history of immunizations with pneumococcal vaccines; determination of IgM, IgG, IgA, and IgE concentrations; measurement of anti-pneumococcal polysaccharide antibody levels by ELISA and expression of CD27, IgD, and IgM on peripheral CD19(+)B cells by flow cytometry to determine the proportions of naive, IgM-memory B cells, and class-switched memory B cells. RESULTS: Patients were classified as having a SAD to either pure polysaccharides (PPV-SAD) or to conjugate polysaccharides (PCV-SAD) based on the number of polysaccharides to which they developed an adequate antibody response. A normal response to only 2 or fewer of 7 PCV or PPV serotypes was considered as evidence of SAD. Forty-one patients without SAD and 26 with SAD were identified. IgM-memory B cells were low in 3 of 41 patients without SAD; in 3 of 5 PPV-SAD patients; and in 10 of 21 PCV-SAD patients. Class-switched memory B cells were low in 19 of 41 patients without SAD; in all 5 patients with PPV-SAD; and in 11 of 21PCV-SAD patients. CONCLUSIONS: Patients with recurrent infection with or without SAD may have low IgM- and/or class-switched memory B cells. Ongoing research aims to determine the prognostic implications of these differences in patients with SAD.

Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology.

A major diagnostic intervention in the consideration of many patients suspected to have primary immunodeficiency diseases (PIDDs) is the application and interpretation of vaccination. Specifically, the antibody response to antigenic challenge with vaccines can provide substantive insight into the status of human immune function. There are numerous vaccines that are commonly used in healthy individuals, as well as others that are available for specialized applications. Both can potentially be used to facilitate consideration of PIDD. However, the application of vaccines and interpretation of antibody responses in this context are complex. These rely on consideration of numerous existing specific studies, interpolation of data from healthy populations, current diagnostic guidelines, and expert subspecialist practice. This document represents an attempt of a working group of the American Academy of Allergy, Asthma & Immunology to provide further guidance and synthesis in this use of vaccination for diagnostic purposes in consideration of PIDD, as well as to identify key areas for further research.

Congenital alterations of NEMO glutamic acid 223 result in hypohidrotic ectodermal dysplasia and immunodeficiency with normal serum IgG levels.

BACKGROUND: Hypomorphic mutations in the nuclear factor-κB (NF-κB) essential modulator (NEMO) gene result in a variable syndrome of somatic and immunologic abnormalities. Clinically relevant genotype-phenotype associations are essential to understanding this complex disease. OBJECTIVE: To study 2 unrelated boys with novel NEMO mutations altering codon 223 for similarity in phenotype in consideration of potential genotype-phenotype associations. METHODS: Clinical and laboratory features, including cell counts, immunoglobulin quantity and quality, natural killer cell cytotoxicity, and Toll-like and tumor necrosis factor receptor signaling, were evaluated. Because both mutations affected NEMO codon 223 and were novel, consideration was given to new potential genotype-phenotype associations. RESULTS: Both patients were diagnosed as having hypohidrotic ectodermal dysplasia and had severe or recurrent infections. One had recurrent sinopulmonary infections and the other necrotizing soft tissue methicillin-resistant Staphylococcus aureus infection and Streptococcus anginosus subdural empyema with bacteremia. NEMO gene sequence demonstrated a 3-nucleotide deletion (c.667_669delGAG) in one patient and a substitution (667G>A) in the other. These findings predict either the deletion of NEMO glutamic acid 223 or it being replaced with lysine, respectively. Both patients had normal serum IgG levels but poor specific antibodies. Natural killer cell cytotoxicity and Toll-like and tumor necrosis factor receptor signaling were also impaired. Serious bacterial infection did not occur in both patients after immunoglobulin replacement therapy. CONCLUSIONS: Two different novel mutations affecting NEMO glutamic acid 223 resulted in clinically relevant similar phenotypes, providing further evidence to support genotype-phenotype correlations in this disease. They suggest NEMO residue 223 is required for ectodermal development and immunity and is apparently dispensable for quantitative IgG production but may be required for specific antibody production.

Exploring the Impact of Ketodeoxynonulosonic Acid in Host-Pathogen Interactions Using Uptake and Surface Display by Nontypeable Haemophilus influenzae.

Surface expression of the common vertebrate sialic acid (Sia) N-acetylneuraminic acid (Neu5Ac) by commensal and pathogenic microbes appears structurally to represent "molecular mimicry" of host sialoglycans, facilitating multiple mechanisms of host immune evasion. In contrast, ketodeoxynonulosonic acid (Kdn) is a more ancestral Sia also present in prokaryotic glycoconjugates that are structurally quite distinct from vertebrate sialoglycans. We detected human antibodies against Kdn-terminated glycans, and sialoglycan microarray studies found these anti-Kdn antibodies to be directed against Kdn-sialoglycans structurally similar to those on human cell surface Neu5Ac-sialoglycans. Anti-Kdn-glycan antibodies appear during infancy in a pattern similar to those generated following incorporation of the nonhuman Sia N-glycolylneuraminic acid (Neu5Gc) onto the surface of nontypeable Haemophilus influenzae (NTHi), a human commensal and opportunistic pathogen. NTHi grown in the presence of free Kdn took up and incorporated the Sia into its lipooligosaccharide (LOS). Surface display of the Kdn within NTHi LOS blunted several virulence attributes of the pathogen, including Neu5Ac-mediated resistance to complement and whole blood killing, complement C3 deposition, IgM binding, and engagement of Siglec-9. Upper airway administration of Kdn reduced NTHi infection in human-like Cmah null (Neu5Gc-deficient) mice that express a Neu5Ac-rich sialome. We propose a mechanism for the induction of anti-Kdn antibodies in humans, suggesting that Kdn could be a natural and/or therapeutic "Trojan horse" that impairs colonization and virulence phenotypes of free Neu5Ac-assimilating human pathogens.IMPORTANCE All cells in vertebrates are coated with a dense array of glycans often capped with sugars called sialic acids. Sialic acids have many functions, including serving as a signal for recognition of "self" cells by the immune system, thereby guiding an appropriate immune response against foreign "nonself" and/or damaged cells. Several pathogenic bacteria have evolved mechanisms to cloak themselves with sialic acids and evade immune responses. Here we explore a type of sialic acid called "Kdn" (ketodeoxynonulosonic acid) that has not received much attention in the past and compare and contrast how it interacts with the immune system. Our results show potential for the use of Kdn as a natural intervention against pathogenic bacteria that take up and coat themselves with external sialic acid from the environment.

Bronchiectasis in Primary Antibody Deficiencies: A Multidisciplinary Approach.

Bronchiectasis, the presence of bronchial wall thickening with airway dilatation, is a particularly challenging complication of primary antibody deficiencies. While susceptibility to infections may be the primary factor leading to the development of bronchiectasis in these patients, the condition may develop in the absence of known infections. Once bronchiectasis is present, the lungs are subject to a progressive cycle involving both infectious and non-infectious factors. If bronchiectasis is not identified or not managed appropriately, the cycle proceeds unchecked and yields advanced and permanent lung damage. Severe symptoms may limit exercise tolerance, require frequent hospitalizations, profoundly impair quality of life (QOL), and lead to early death. This review article focuses on the appropriate identification and management of bronchiectasis in patients with primary antibody deficiencies. The underlying immune deficiency and the bronchiectasis need to be treated from combined immunology and pulmonary perspectives, reflected in this review by experts from both fields. An aggressive multidisciplinary approach may reduce exacerbations and slow the progression of permanent lung damage.

BCG: a vaccine with multiple faces.

BCG has been recommended because of its efficacy against disseminated and meningeal tuberculosis. The BCG vaccine has other mechanisms of action besides tuberculosis protection, with immunomodulatory properties that are now being discovered. Reports have shown a significant protective effect against leprosy. Randomized controlled trials suggest that BCG vaccine has beneficial heterologous (nonspecific) effects on mortality in some developing countries. BCG immunotherapy is considered the gold standard adjuvant treatment for non-muscle-invasive bladder cancer. BCG vaccine has also been tested as treatment for diabetes and multiple sclerosis. Erythema of the BCG site is recognized as a clinical clue in Kawasaki disease. BCG administration in the immunodeficient patient is associated with local BCG disease (BCGitis) or disseminated BCG disease (BCGosis) with fatal consequences. BCG administration has been associated with the development of autoimmunity. We present a brief review of the diverse facets of the vaccine, with the discovery of its new modes of action providing new perspectives on this old, multifaceted and controversial vaccine.

Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a Coronin-1A mutation and a chromosome 16p11.2 deletion.

Defects causing severe combined immunodeficiency (SCID) have been reported in pathways mediating antigen receptor rearrangement, antigen receptor and cytokine signaling, and purine metabolism. Recognizing that the actin regulator Coronin-1A is essential for development of a normal peripheral T cell compartment in mouse models, we identified absence of Coronin-1A in a girl with T-B+NK+ SCID who suffered recurrent infections including severe post-vaccination varicella at age 13 months. Murine Coronin-1A is essential for the release of T cells from the thymus, consistent with the paradoxically detectable thymus in our patient. Molecular analysis revealed a 2 bp deletion in the paternal CORO1A coding sequence paired with a 600 kb de novo deletion encompassing CORO1A on the maternal allele. This genomic region at 16p11.2 is subject to recurrent copy number variations associated with autism spectrum disorders, including attention deficit and hyperactivity, present in our patient. This case highlights the first link between actin cytoskeleton regulation and SCID.

Specific Antibody Deficiencies in Clinical Practice.

Specific antibody deficiency (SAD) is defined as the inability to mount an antibody response to purified Streptococcus pneumoniae capsular polysaccharide antigens in the presence of normal immunoglobulin concentrations and normal antibody responses to protein antigens. In this review, we discuss the difficulties in using presently available testing methods to adequately define SAD. The fact that there are different forms of SADs to pneumococcal surface polysaccharides is detailed. The diagnostic and therapeutic implications of recognizing that, in addition to SAD, there are other forms of SAD in the response to S. pneumoniae polysaccharides are described in detail. The conclusion of this review is that assessment of immunity and therapeutic actions to deal with SADs need to be based on clinical evidence rather than solely on arbitrarily defined antibody responses.

Specific Antibody Deficiencies.

Patients with specific antibody deficiency (SAD) have a deficient immunologic response to polysaccharide antigens. Such patients experience sinopulmonary infections with increased frequency, duration, or severity compared with the general population. SAD is definitively diagnosed by immunologic challenge with a pure polysaccharide vaccine in patients 2 years old and older who have otherwise intact immunity, using the 23-valent pneumococcal polysaccharide vaccine as the current gold standard. Specific antibody deficiencies comprise multiple immunologic phenotypes. Treatment must be tailored based on the severity of symptoms. Most patients have a good prognosis. The deficiency may resolve over time, especially in children.