Physiology of IgA and IgA Deficiency

Although secretory immunoglobulin A (IgA) is important in mucosal immunity, selective IgA deficiency is the most common primary immunodeficiency of humans. In most cases this defect is not associated with any illness. The reasons for this are unknown, but other immunological compensations might provide sufficient or complete restitution. Alternatively, it is possible that IgA deficiency alone may not predispose to disease, but additional immunological abnormalities might be present in symptomatic individuals. Some IgA-deficient individuals have a reduced antibody response to immunizations (even with normal IgG and IgM levels) and others have deficient responses to bacterial polysaccharides when IgG subclass levels are normal. The physiological role of IgA, the frequency and causes of IgA deficiency, the diseases associated with its absence, and current limited understanding of the pathogenesis of selective IgA deficiency will be reviewed.     

Selective IgA Deficiency

Introduction  

Immunoglobulin A (IgA) deficiency is the most common primary immunodeficiency defined as decreased serum level of IgA in the presence of normal levels of other immunoglobulin isotypes. Most individuals with IgA deficiency are asymptomatic and identified coincidentally. However, some patients may present with recurrent infections of the respiratory and gastrointestinal tracts, allergic disorders, and autoimmune manifestations.     

Virus Antibody Levels and IgA Deficiency

IgA-deficient blood donors and their age- and sex-matched controls were compared for the occurrence of complement-fixing antibodies in serum against several viruses. The level in the IgA-deficient persons was slightly higher against several respiratory pathogens (adenoviruses, type B influenza virus, parainfluenza virus, and respiratory syncytial virus) that give rise to localized infections, and against coxsackie B group of viruses. No corresponding difference was observed in mumps, varicella, and cytomegalovirus infections, where viraemia is a characteristic feature, or in Mycoplasma pneumoniae infection.     

Anti-IgA in Selective IgA Deficiency

Anti-IgA antibodies were found in 14 of 33 (42%) IgA-deficient donors. In healthy IgA-deficient blood donors anti-IgA appeared associated with the presence of HLA DR3. The antibodies were mainly of the IgG1 and, in high-titred sera, IgG4 subclasses. Sera containing high-titred anti-IgA selectively impaired IgA synthesis in vitro as induced by direct and indirect polyclonal B-cell activators. These antibodies may play a role in the pathogenesis and/or the maintenance of IgA deficiency.     

Gut-Associated IgA Deficiency in Lepromatous Leprosy

Sera, intestinal secretions and intestinal biopsies were collected from twelve biopsy-proved lepromatous leprosy patients with the help of a capsule invented by Roy Choudhury. Sera from another twenty-five proved lepromatous cases were also included. Sera and intestinal aspirates from twenty-five normal subjects and twenty patients wish intestinal tuberculosis were also taken as controls. Acid-fast organisms, morphologically resembling Mycobacterium leprae , were detected in the intestinal aspirates of only two leprosy patients. Immunoglobulin levels in their sera and elevation secretions were estimated by the single radial immunodiffusion technique. Significant elevation of serum IgG, IgA and IgM. selective IgA deficiency in intestinal aspirates and flattening of intestinal villi along with mononuclear cell infiltration were conspicuous observations in the leprosy group. On the other hand, the patients with intestinal tuberculosis showed elevation of the IgG level in serum as well as in the intestinal secretions. It was postulated that persistent challenge by M. leprae or its antigens to the IgA immunocytes of the intestinal epithelium might have induced tolerance leading to IgA deficiency and subsequent subtotal atrophy of the intestinal villi in the patients with lepromatous leprosy.     

Selective IgA Deficiency in Children in Israel

IgA deficiency is the most common human primary immune-deficiency. We evaluated the clinical and immunological characteristics of selective IgA deficiency in children in Israel. The study group included 63 children diagnosed with IgA deficiency from 1987 to 2005. Mean follow-up time per child was 10.6 years. Average age at diagnosis was 10.5 years. In one child, the IgA deficiency was transient. Infectious diseases, mainly recurrent pneumonia and ear infection, were common and occurred in 25 patients (39.7%). Allergic diseases were documented in 20 (31.7%) of our patients. Thirteen children (20.6%) had autoimmune diseases. Malignancies were diagnosed in three children (4.8%), an association that has not been reported in previous series. IgA deficiency appears to be a risk factor for infections, allergic diseases, autoimmune conditions, and malignancy.     

IgA Deficiency: Correlation Between Clinical and Immunological Phenotypes

Background  IgA deficiency (IGAD) is the most common primary antibody deficiency. Although many affected individuals have no apparent symptom, selected patients suffer from recurrent mucosal infections, allergies, and autoimmune diseases. We aimed to investigate the clinical features in relation to immune function of Iranian patients with symptomatic IGAD. Methods  Thirty-seven patients (21 male and 16 female), aged 4–32 years, were evaluated in this study. Patients were followed for a total of 131 patient years with a mean follow-up of 3.5 years per patient. Results  The most prevalent presentations were recurrent infections occurring in 27 subjects, followed by allergy in eight cases and autoimmunity in two patients. However, during the follow-up period, 35 patients developed infections in respiratory and gastrointestinal tracts, necessitating medical care. Apart from infections, allergy was the most frequent complaint (31 cases); the major features were asthma, atopic dermatitis, and allergic rhinoconjunctivitis. Autoimmune diseases were documented in ten cases; thyroiditis was the most common. In 31 patients who received unconjugated pneumococcal polyvalent vaccine, antibody response against polysaccharide antigen was measured before and 28 days after vaccination. One fourth of vaccinated patients were hyporesponsive to vaccine; four of these patients developed bronchiectasis. The patients with IGAD were classified into two groups: group 1 (14 cases) consisted of patients with IGAD and other associated immune defects, such as immunoglobulin G (IgG) subclass deficiency and defective specific antibody production. Group 2 (23 cases) had isolated IGAD without other immunological abnormalities. There was a significantly increased number of lower respiratory tract infections in group 1 compared with group 2 (P = 0.006). Moreover, four patients of group 1 had bronchiectasis whereas none of the patients in group 2 developed this complication (P = 0.015). Conclusion  Subclassification of IGAD regarding the existence of associated immune defects is useful in terms of morbidity and planning for medical care. IgA-deficient patients with concomitant immune defects such as defects in specific antibody production have higher rates of recurrent infections and bronchiectasis, which necessitates more effective monitoring.     

Prophylaxis and Treatment of Influenza Virus Infection

Influenza virus infections remain an important cause of morbidity and mortality. Furthermore, a recurrence of pandemic influenza remains a real possibility. There are now effective ways to both prevent and treat influenza. Prevention of infection is most effectively accomplished by vaccination. Vaccination with the inactivated, intramuscular influenza vaccine has been clearly demonstrated to reduce serious morbidity and mortality associated with influenza infection, especially in groups of patients at high risk (e.g. the elderly). However, the inactivated, intramuscular vaccine does not strongly induce cell-mediated or mucosal immune responses, and protection induced by the vaccine is highly strain specific. Live, attenuated influenza vaccines administered intranasally have been studied in clinical trials and shown to elicit stronger mucosal and cell-mediated immune responses. Live, attenuated vaccines appear to be more effective for inducing protective immunity in children or the elderly than inactivated, intramuscular vaccines. Additionally, novel vaccine methodologies employing conserved com-ponents of influenza virus or viral DNA are being developed. Preclinical studies suggest that these approaches may lead to methods of vaccination that could induce immunity against diverse strains or subtypes of influenza. Because of the limitations of vaccination, antiviral therapy continues to play an important role in the control of influenza. Two major classes of antivirais have demonstrated ability to prevent or treat influenza in clinical trials: the adaman-tanes and the neuraminidase inhibitors. The adamantanes (amantadine and rimantadine) have been in use for many years. They inhibit viral uncoating by blocking the proton channel activity of the influenza A viral M2 protein. Limitations of the adamantanes include lack of activity against influenza B, toxicity (especially in the elderly), and the rapid development of resistance. The neuraminidase inhibitors were designed to interfere with the conserved sialic acid binding site of the viral neuraminidase and act against both influenza A and B with a high degree of specificity when administered by the oral (oseltamivir) or inhaled (zanamivir) route. The neuraminidase inhibitors have relatively low toxicity, and viral resistance to these inhibitors appears to be uncommon. Additional novel antivirals that target other phases of the life cycle of influenza are in preclinical development. For example, recombinant collectins inhibit replication of influenza by binding to the viral haemagglutinin as well as altering phagocyte responses to the virus. Recombinant techniques have been used for generation of antiviral proteins (e.g. modified collectins) or oligonucleotides. Greater understanding of the biology of influenza viruses has already resulted in significant advances in the management of this important pathogen. Further advances in vaccination and antiviral therapy of influenza should remain a high priority.     

Intranasal Delivery of an IgA Monoclonal Antibody Effective against Sublethal H5N1 Influenza Virus Infection in Mice

Highly pathogenic avian H5N1 influenza viruses are endemic in poultry in Asia and pose a pandemic threat to humans. Since the deployment of vaccines against a pandemic strain may take several months, adequate antiviral alternatives are needed to minimize the effects and the spread of the disease. Passive immunotherapy is regarded as a viable alternative. Here, we show the development of an IgA monoclonal antibody (DPJY01 MAb) specific to H5 hemagglutinin. The DPJY01 MAb showed a broad hemagglutination inhibition (HI) profile against Asian H5N1 viruses of clades 0, 1.0, 2.1, 2.2, and 2.3 and also against H5 wild bird influenza viruses of the North American and Eurasian lineages. DPJY01 MAb displayed also high neutralization activity in vitro and in vivo. In mice, DPJY01 MAb provided protection via a single dose administered intranasally before or after inoculation with a sublethal dose of H5N1 viruses of clades 1.0 and 2.2. Pretreatment with 50 mg of DPJY01 MAb kg of body weight at either 24, 48, or 72 h before highly pathogenic H5N1 virus (A/Vietnam/1203/2004 [H5N1]) inoculation resulted in complete protection. Treatment with 50 mg/kg at either at 24, 48, or 72 h after H5N1 inoculation provided 100%, 80%, and 60% protection, respectively. These studies highlight the potential use of DPJY01 MAb as an intranasal antiviral treatment for H5N1 influenza virus infections.Influenza type A viruses are negative-sense segmented RNA viruses that belong to the family Orthomyxoviridae (11). They are further subdivided into subtypes based on the antigenic properties of the two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). Among these subtypes, the highly pathogenic avian H5N1 influenza viruses have been intensively studied since the first report of lethal human infections in 1997 (36). H5N1 viruses continue to circulate in poultry in Asia and occasionally are transmitted from birds to humans, posing a potential pandemic threat (1). As of 6 April 2010, the World Health Organization (WHO) had reported 493 human infections with 292 deaths, a fatality rate exceeding 60%. These strains have shown significant evolutionary changes and are currently divided into 10 HA clades (36). Among these clades, clade 2 is further classified into five subclades (2.1 to 2.5), and within each subclade there are several lineages (35). Clade 2.1 is predominant in Indonesia, the country in which H5N1 has become endemic and in which the highest number of human infections and associated fatalities have been reported. In Indonesia, of the 163 cases confirmed to date by the WHO, 135 have been fatal. The latest human infections with H5N1 viruses have been reported in Egypt, where viruses from clade 2.2.1 are endemic. In Egypt since 2006, H5N1 viruses have been identified as the causative agent in 109 human infections with 34 deaths according to the WHO. More importantly, some of these strains have developed resistance to available antiviral drugs (17, 21). For example, most clade 1 H5N1 viruses are resistant to adamantanes (10), and oseltamivir-resistant H5N1 viruses with neuraminidase mutations (H274Y and N294S) have been also identified in infected patients during or after treatment (7, 12). These limitations and others, such as the poor immunogenicity of H5N1 vaccines (3, 16, 26, 31), call for the development of alternative intervention strategies.Several groups have reported the development of monoclonal antibodies (MAbs) against the HA of influenza viruses, particularly against the H1, H3, and H5 subtypes (9, 14, 38). Some of these MAbs have broad subtype cross-reactions (38). Human and mouse monoclonal antibodies against H5 HA have been shown to provide protection against lethal infection in a mouse model (4, 20, 24). These anti-H5 MAbs are usually of the IgG1 or IgG2a subtypes and are administered by parenteral routes. Retrospective studies have suggested that those patients with influenza pneumonia during the 1918 Spanish influenza pandemic who received influenza convalescent-phase human blood products may have experienced a reduction in the risk of death (15), and H5N1-infected patients treated with convalescent H5N1 plasma recovered from the infection (39). Therefore, passive antibody immunotherapy is an attractive and potentially efficient alternative for the treatment of H5N1 infections. To our knowledge, intranasal administration of antibodies against H5N1 has not been reported. Although intranasal administration of drugs depends largely on the health status of the patient, it does represent an alternative intervention strategy. Intranasal administration of antibodies would allow the antibodies to directly reach their target in the respiratory track, which is the major site for influenza virus replication in humans and other mammals (29, 33). IgA-mediated neutralization monoclonal antibody therapy against H5N1 has not been reported, and only a few IgA MAbs against A/Puerto Rico/8/34 (H1N1) have been reported to show antiviral activity when given intravenously (2). In this study, we generated an IgA monoclonal antibody (DPJY01) with a broad HI profile and high neutralization activity against the H5N1 virus in vitro and in vivo. Remarkably, DPJY01 provided protection against sublethal H5N1 infection after a single dose through intranasal administration.     

B-lymphocyte Subpopulations in Patients with Selective IgA Deficiency

Introduction

Selective deficiency IgA (IgAD) is the most common primary abnormality of immunoglobulin production with unknown pathophysiology. It is genetically related to common variable immunodeficiency (CVID), where besides IgA also IgG and frequently IgM serum levels are decreased. In this study we focused on determination of B-lymphocyte developmental stages and searching for similarities between CVID and IgAD.

Materials and Methods

Using flow cytometry we determined major lymphocyte subpopulations and B-lymphocyte subsets: na?ve (CD27^-IgD⁺), marginal zone cells (CD27⁺IgD⁺), class-switched memory cells (CD27⁺IgD^-), ??double-negative?? B cells (CD27^-IgD^-), transitional cells (IgM⁺⁺CD38⁺⁺), plasmablasts (CD38⁺⁺⁺IgM⁺ or IgM^-), and CD21^lowCD38^low cells in 80 patients with IgAD, 48 patients with CVID, and 80 control persons.

Results

Compared to healthy controls, a decrease in the absolute number and frequency of CD4+ cells (both?P?P?=?0.035) as well as plasmablasts (P?lowCD38^low subset (P?=?0.007) was observed in IgAD patients compared to control persons. No significant differences were observed in the remaining B-cell developmental subsets. A decrease in CD27⁺IgD^- (<0.4% of peripheral blood lymphocytes), frequently observed in CVID patients and also previously reported in IgAD, was found in only five patients (6%) with IgAD, two of them being first-degree relatives of CVID patients.

Conclusion

Our results show a decrease of terminally differentiated B-lymphocyte subsets in patients with IgAD, similar as previously found in patients with CVID, but these results are less expressed than in CVID patients.     

Autoimmunity in IgA Deficiency: Revisiting the Role of IgA as a Silent Housekeeper

Both systemic and organ-specific autoimmune diseases are major manifestations of IgA deficiency (IgAD), the most common primary immunodeficiency. In addition, to discuss the clinical findings of IgAD patients, we proposed a hypothesis to explain the high association with autoimmune phenomena. Based on observations, interactions of monomeric IgA with FcαRI result in a partial phosphorylation of FcRγ-associated FcαRI, notably in the immunoreceptor tyrosine-based activation motif (ITAM) inducing the recruitment of the SHP-1 tyrosine phosphatase. This leads to deactivation of several activating pathways of the immune system including immunoreceptors that bear ITAM motif and ITAM-independent receptors. Consequently, inflammatory reactions and auto-immune process would be prevented.     

The First Purine Nucleoside Phosphorylase Deficiency Patient Resembling IgA Deficiency and a Review of the Literature

Purine nucleoside phosphorylase (PNP) deficiency is a rare autosomal recessive primary immunodeficiency disorder characterized by decreased numbers of T-cells, variable B-cell abnormalities, decreased amount of serum uric acid and PNP enzyme activity. The affected patients usually present with recurrent infections, neurological dysfunction and autoimmune phenomena. In this study, whole-exome sequencing was used to detect mutation in the case suspected of having primary immunodeficiency. We found a homozygous mutation in PNP gene in a girl who is the third case from the national Iranian registry. She had combined immunodeficiency, autoimmune hemolytic anemia and a history of recurrent infections. She developed no neurological dysfunction. She died at the age of 11 after a severe chicken pox infection. PNP deficiency should be considered in late-onset children with recurrent infections, autoimmune disorders without typical neurologic impairment.     

Massive Empyema Associated With Transient Hypogammaglobulinemia of Infancy and IgA Deficiency

Transient hypogammaglobulinemia of infancy (THI) is originally defined as a physiological maturation defect of immunoglobulin G (IgG) production that occurs at 3-6 months of age and lasts until 18 to 36 months of age. We report here on a 22-month-old child with THI and IgA deficiency, who had massive pneumococcal empyema. Her depressed IgG level returned to normal within 6 months, but IgA level was still low at 6 yr of age. Although THI is an age-dependent and self-limiting disorder, severe infection that includes an atypical presentation of an infection may occur in some patients and this requires evaluation with immunologic study.     

Point-of-Care Testing for Group A Streptococcus Infection and Influenza

Point of care (POC) testing has emerged as a critical tool in the early and rapid diagnosis and treatment of infectious diseases. While the mainstay of these POC tests has been lateral-flow-based antigen detection assays, recent technological advances in nucleic acid detection combined with regulatory changes has allowed more sensitive detection of infectious etiologies in the near-patient setting. This advancement is particularly impactful in the ambulatory setting, where rapid diagnosis can ensure appropriate treatment at the early stages of infection, both preventing more serious sequelae and also improving physician workflow and patient satisfaction. Along with this new technology come concerns about quality of testing, nucleic acid contamination, and the appropriate use of POC tests. This review covers the clinical manifestations of disease, the current state of POC testing, and the impact of molecular testing for both group A Streptococcus infection and influenza.     

Influenza Virus Infection and Risk of Acute Myocardial Infarction

Increasing evidences have shown that pathogens might promote atherosclerosis and trigger acute myocardial infarction (AMI). But the conclusions from various studies on the correlation between previous influenza virus (IV) infection and AMI were inconsistent. We conducted a case-control study to assess the association of previous IV infection and AMI. Questionnaire survey was conducted to collect information about demographic characteristics and heart disease risk factors. Fasting blood sample was obtained to measure IgG antibodies to influenza virus A(IV-A), influenza virus B(IV-B), cytomegalovirus (CMV), herpes simplex virus type-1 (HSV-1) and type-2 (HSV-2), adenovirus (ADV), rubella virus (RV) and Chlamydia pneumoniae (CP) and measure the level of some biochemistry markers. Compared to controls, cases were more likely to have positive IgG antibodies to IV-A and IV-B (IV-A: OR, 3.3; 95%CI, 1.5 to 7.4; IV-B: OR, 17.2; 95%CI, 7.7 to 38.0). After adjustment for potential confounding variables, the risk of AMI was still associated with the presence of IgG antibodies to IV-A (adjusted OR, 7.5; 95%CI, 1.3 to 43.0) and IV-B (adjusted OR, 27.3; 95%CI, 6.6 to 113.8). The study supported the hypothesis that previous IV infection took part in the development of atherosclerosis and trigger the occurrence of AMI.     

炎性体及其在流感病毒感染过程中的作用

炎性体是胞液中感受危险信号、启动介导下游免疫防御或细胞死亡(pyroptosis)的多分子复合物,是细胞内天然免疫的重要受承信号转导的中介体.炎性体识别流感病毒后诱导先天免疫反应甚至pyroptosis样细胞死亡.流感病毒高尔基体表达的M2蛋白和P2X7、ATP、ROS在炎性体的调节过程中发挥了重要作用,微生物也可以通...     

Efficacy of Influenza Haemagglutinin and Nucleoprotein as Protective Antigens against Influenza Virus Infection in Mice

Influenza nucleoprotein (NP)-specific cytotoxic T lymphocytes (CTL) stimulated by immunization of mice with VV-PR8-NP6, a recombinant vaccinia virus expressing A/PR/8/34 NP, did not protect mice against challenge with A/PR/8/34 4 days later. Neither were secondary NP-specific CTL stimulated by reimmunization able to protect mice. These results contrast with the ability of transferred, in vitro-cultured and stimulated, NP-specific CTL to protect recipient mice from challenge with A/PR/8/34. Immunization of mice with a recombinant vaccinia virus expressing A/PR/8/34 HA protected mice challenged 4 days later, either via the small amount of antibody already present, or via HA-specific CTL that would have to be more efficient than NP-specific CTL in either trafficking to the infected lung or in effector function.