Absence Of IgA Research Articles

IgA-mediated control of host-microbial interaction during weaning reaction influences gut inflammation.

The mechanisms of how host-microbe mutualistic relationships are established at weaning contingently upon B-cell surveillance remain inadequately elucidated. We found that CD138+ plasmacyte (PC)-mediated promotion of IgA response regulates the symbiosis between Bacteroides uniformis (B. uniformis) and the host during the weaning period. The IgA-skewed response of CD138+ PCs is essential for B. uniformis to occupy a defined gut luminal niche, thereby fostering stable colonization. Furthermore, B. uniformis within the natural gut niche was perturbed in the absence of IgA, resulting in exacerbated gut inflammation in IgA-deficient mice and weaned piglets. Thus, we propose that the priming and maintenance of intestinal IgA response from CD138+ PCs are required for host-microbial symbiosis, whereas the perturbation of which would enhance inflammation in weaning process.

A Case Report of Hyper-IgM Syndrome Patient with Normal Serum IgA Level

Hyper IgM syndromes are a group of disorders characterized by defective T and B cell interactions resulting in the lack of Immunoglobulin class switching. The most common hyper IgM syndrome is CD40 ligand (CD40L) deficiency. Patients with CD40L deficiency present with recurrent infection, neutropenia, and autoimmunity. These patients typically have absent serum IgA and IgG due to the class switch defect. Here we present a case of CD40L deficiency who presented with oral ulcers, failure to thrive, and recurrent fever. His laboratory evaluation was notable for intermittent neutropenia, elevated IgM (397mg/dl), normal IgA (78mg/dl) and low IgG (51mg/dl). Antibody responses to tetanus and measles were undetectable despite full vaccination. Whole exome sequencing showed a likely pathologic variant in CD40LG (c.674 T>C, p.L225S). This case highlights the importance of considering the diagnosis of hyper IgM syndrome in the appropriate clinical setting, even if the patient has a normal serum IgA level.

New diagnosis of late onset combined immune deficiency in an adult with associated 16p13.3 duplication syndrome

Background16p13 duplication syndrome is a rare chromosomal disorder that manifests with neurocognitive delay/autism, dysmorphic features, and cardiac defects. Severe pneumonia has been documented in patients with this disorder and mostly attributed to abnormal anatomy. To date, no phenotype of immune deficiency has been linked to 16p13 duplication syndrome. Case reportHere we report a case of a 57-year-old female with history of cleft palate, dysmorphia, autism, seizure disorder, uncharacterized myopathic disorder, chronic diarrhea, volvulus, recurrent pneumonias and shingles, and a previous diagnosis of common variable immune deficiency (CVID). Patient presented to our clinic to establish care in the setting of persistent disseminated verruca and recurrent UTIs. She had hypogammaglobulinemia with absent IgA and IgM but normal IgG while on Immunoglobulin infusion (IVIG). Immunophenotyping demonstrated T and NK cell lymphopenia (CD4: 225 cells/µL; CD8: 71 cells/µL; CD56: 29 cells/µL) and absent B cells. Lymphocyte proliferation with antigen and mitogen stimulation was normal. Immune gene panel testing demonstrated three copy number variants (CNV) in CLCN7, HPS3, and SLX4 (all on Chr16) and heterozygous variants of unknown significant (VUS) in FANCI, HPS3, and UNC45A. Chromosomal microarray analysis demonstrated 4.8Mbp copy number gain in the 16p13.3 region (Chr16:383485-5220007) with a terminal 293kbp copy number loss. She remained on IVIG but passed away before additional advanced immune studies could be done. DiscussionThere are few microduplication syndromes that are associated with immune deficiencies including 16p11.2, 19p13, 20p12.2, 22q11.2, and MECP2 duplication. We established a new diagnosis of 16p13.3 duplication syndrome in an adult patient with recurrent cutaneous viral infections, pneumonias, and laboratory features consistent with late onset combined immune deficiency (LOCID). This case report adds to the existing literature on duplication syndromes and associated immune abnormalities.

Lupus nephritis with clinical and laboratory features of humoral immune deficiency in a 29-year-old female with a novel NCF1 variant consistent with autosomal recessive chronic granulomatous disease

Chronic Granulomatous Disease (CGD) is a rare, inherited disorder of the innate immune system characterized by defects in the phagocyte NADPH oxidase complex. This results in poor phagocyte function causing frequent infections (bacterial and fungal) and chronic inflammation. Here we discuss a rare presentation of lupus nephritis and antibody deficiency in an adult female patient with a novel homozygous nonsense mutation in the NCF-1 gene causing autosomal recessive CGD.Our patient is a 29-year-old female with history of ITP, biopsy-confirmed lupus nephritis, systemic lupus erythematosus (SLE), idiopathic avascular necrosis of the hip, and previous diagnosis of common variable immune deficiency (CVID) treated with Immunoglobulin replacement therapy (IVIG). She presented to our clinic to establish care in the setting of persistent skin abscesses/cellulitis, poor wound healing, necrotic lymphadenitis, and recurrent urinary tract infections and pneumonia despite years of IVIG therapy. She had near-normal total IgG, absent IgA and IgE, and protective vaccine antibody titers (pneumococcus, diphtheria, and tetanus) prior to the start of IVIG. Immunophenotyping demonstrated quantitatively normal number of total B cells, absent CD27+ memory B cells, and normal T cell subsets. She had reassuring lymphocyte proliferation with mitogen stimulation and normal TLR function. Dihydrorhodamine (DHR) flow cytometric assay demonstrated abnormally low neutrophil oxidative burst activity. Gene sequencing revealed homozygous nonsense mutation in the NCF-1 gene (c.75-76del; pY26Hfs*26) and a pathogenic heterozygous variant in FANCM (c.3732-3735dup; p. Leu1246Asnfs*8). She was started on daily prophylactic trimethoprim-sulfamethoxazole and itraconazole. She has marked decrease in infections/hospitalizations and her lupus nephritis is well controlled with hydroxy-chloroquine. She is being referred to the NIH for HSCT evaluation. The majority of CGD cases in the United States are due to X-linked CGD (70%) and AR variants in NCF1 (20%). While rare, discoid lupus erythematosus and SLE have been documented with X-linked forms of CGD. Similarly, there are few case reports of antibody deficiency in patients with CGD. This is the first documented case of AR CGD with SLE/lupus nephritis and humoral immune defects. Additionally, we report a disease-causing, novel variant in the NCF1 gene. This case report adds to the existing literature on CGD and associated diseases.

IgG and IgA Antibodies Post SARS-CoV-2 Vaccine in the Breast Milk and Sera of Breastfeeding Women.

The COVID-19 pandemic has carried massive global health and economic burden that is currently counteracted by a challenging anti-COVID-19 vaccination campaign. Indeed, mass vaccination against COVID-19 is expected to be the most efficacious intervention to mitigate the pandemic successfully. The primary objective of the present study is to test the presence of neutralizing anti-SARS-CoV-2 antibodies (IgA and IgG) in the breast milk and sera samples from vaccinated women at least 20 days after the complete vaccine cycle. A secondary aim is to compare the IgG antibodies level in maternal serum and breast milk. The third target is to evaluate the presence of the IgG antibodies in breast milk after several weeks from the vaccination. Finally, we collected information on the health status of infants in the days following maternal vaccination. Forty-two mothers were enrolled in the study. Thirty-six received the Pfizer/BioNTech vaccine, four the Astra Zeneca vaccine, one the Moderna vaccine and another woman Astra Zeneca in the first dose and Pfizer/BioNTech in the second dose. All 42 milk samples confirmed the presence of anti-SARS-CoV-2 IgG, and none showed IgA presence. Regarding the matched 42 sera samples, 41 samples detected IgG presence, with one sample testing negative and only one positive for seric IgA. None of the 42 infants had fever or changes in sleep or appetite in the seven days following the maternal vaccination. The level of IgG antibodies in milk was, on average, lower than that in maternal serum. According to our analysis, the absence of IgA could suggest a rapid decrease after vaccination even if frequent breastfeeding could favour its persistence. IgG were present in breast milk even 4 months after the second vaccine dose. Information on the immunological characteristics of breast milk could change mothers’ choices regarding breastfeeding.

Successful Treatment of Epidermolysis Bullosa Pruriginosa with Anti-IgE Therapy (Omalizumab): A Case Report and Four Years Follow Up

Importance: Epidermolysis bullosa pruriginosa (EBP) is a rare adult-onset heredo-familial skin disorder. Bullous skin lesions are triggered by intense pruritus, which is the hallmark of the disease. Eosinophilic infiltrates and elevated IgE levels in serum and lesions have been reported, but their pathological role is yet to be determined. Although treatment with anti-IgE therapy (Omalizumab) has been used successfully in autoimmune bullous diseases but not in EBP to our knowledge. Observation: We report a case of a 34-year-old female with adult-onset pruritic and blistering disease of the skin. Sub epidermal blisters with viable roofs and numerous epidermal neutrophils and eosinophilic infiltrate were detected histopathologically; however, the absence of IgA, IgG, IgM, C1q, and C3 deposits made the diagnosis of Epidermolysis bullosa acquisita and Bullous pemphigoid uncertain. Whilst testing for intra-lesional IgE autoantibodies was not performed, total and specific serum IgE concentrations increased during her illness in the absence of an allergic or parasitic disease. Because no improvement in her symptoms was observed with conventional treatments, whole exome sequencing was performed which showed a non-conservative Glycine substitution in the G2481D residue in the COL7A1 gene suggestive of EBP. Off-label use of anti-IgE drug (Omalizumab) was attempted due to severity of her symptoms and elevated levels of IgE. On initiating the treatment, the patient showed a significant improvement in her skin condition; however, a trial to taper off Omalizumab two years later was unsuccessful. Conclusion: This case suggests a possible role of IgE autoantibodies in EBP that requires further research, consolidated by the fact that our patient showed improvement with anti-IgE therapy. Furthermore anti-IgE therapy offers a possible new targeted treatment for EBP in the absence of curative treatments.

A case of primary immunodeficiency: hyper IgM syndrome

Hyper IgM syndrome are group to disorders characterized by elevated serum level of IgM and low or absent serum levels of IgG, IgA and IgE the mechanism of HIGM is immunoglobulin Class-Switch Recombination (CSR) failure and Somatic Hyper Mutation (SHM). This diagnosis should be considered in any patient presenting with hypogammaglobulinemia, with low or absent IgG and IgA and normal or elevated IgM level. In the present case report, this was a 6-year-old male child who had history of recurrent respiratory tract infections who presented with otitis media and persistent fever spikes. Immunoglobulin studies revealed a pattern consistent with hyper IgM.

HIV-1/SIV Humoral Responses in External Secretions

The protective function of mucosal HIV-1- or SIV-specific antibodies against viral infection has stimulated extensive studies of their Ig isotype association with differences in specificity and in effector functions. In contrast to many mucosally acquired microbial infections in which the humoral responses are dominated by induction of secretory IgA (S-IgA), HIV-1/SIV infections stimulate vigorous IgG responses in sera as well as in external secretions but low IgA virus-specific antibodies although the total levels of IgA in these fluids remain unaltered. The diminished or even absent IgA responses to HIV-1/SIV and to other mucosal antigens in external secretions and their replacement with IgG is likely to influence the functionality of mucosal barriers and eliminate antiinflammatory effector functions of IgA antibodies. Furthermore, the polymeric character of S-IgA with 4-8 antigen-binding sites, exquisite resistance to proteolysis and anti-inflammatory potential are of great advantage in mucosal protection. The markedly different effector functions of mucosal antibodies of IgG and IgA isotypes must be considered in the design of HIV-1 vaccines to stimulate S-IgA responses at sites of virus entry and IgG responses in the systemic compartment.

Synergistic convergence of microbiota-specific systemic IgG and secretory IgA

Commensals induce local IgA responses essential to the induction of tolerance to gut microbiota, but it remains unclear whether antimicrobiota responses remain confined to the gut. The aim of this study was to investigate systemic and intestinal responses against the whole microbiota under homeostatic conditions and in the absence of IgA. We analyzed blood and feces from healthy donors, patients with selective IgA deficiency (SIgAd), and patients with common variable immunodeficiency (CVID). Immunoglobulin-coated bacterial repertoires were analyzed by using combined bacterial fluorescence-activated cell sorting and 16S rRNA sequencing. Bacterial lysates were probed by using Western blot analysis with healthy donor sera. Although absent from the healthy gut, serum antimicrobiota IgG are present in healthy subjects and increased in patients with SIgAd. IgG converges with nonoverlapping secretory IgA specificities to target the same bacteria. Each individual subject targets a diverse microbiota repertoire with a proportion that correlates inversely with systemic inflammation. Finally, intravenous immunoglobulin preparations target CVID gut microbiota much less efficiently than healthy microbiota. Secretory IgA and systemic IgG converge to target gut microbiota at the cellular level. SIgAd-associated inflammation is inversely correlated with systemic anticommensal IgG responses, which might serve as a second line of defense. We speculate that patients with SIgAd could benefit from oral IgA supplementation. Our data also suggest that intravenous immunoglobulin preparations can be supplemented with IgG from IgA-deficient patient pools to offer better protection against gut bacterial translocations in patients with CVID.

Clinical Phenotypes of Hyper-IgM Syndromes

The primary immunodeficiency (PID) diseases comprise a heterogeneous group of inherited disorders of immune function. Technical advancements in whole-genome, whole-exome, and RNA-sequencing have seen the explosion of genetic discoveries in the field of PIDs. The present review aims to focus on a group of immunodeficiency disorders associated with elevated levels of IgM (hyper IgM; HIGM) and provides a clinical differential diagnosis. Most patients present for evaluation of immunodeficiency due to recurrent infections, and laboratory studies show either a clear isolated elevation of serum immunoglobulin M (IgM) with low or absent IgG, IgA, and IgE. Alternatively, IgM levels may be normal or moderately elevated while other serum immunoglobulins are reported below the norms for age but not absent. Mechanistically, these disorders are recognized as defects in immunoglobulin (Ig) class switch recombination (CSR). Importantly, to safeguard genetic stability, CSR utilizes elements of the DNA repair machinery including multi-protein complexes involved in mismatch repair (MMR). Therefore, it is not uncommon for defects in the DNA repair machinery, to present with laboratory findings of HIGM. This review will discuss clinical phenotypes associated with congenital defects associated with HIGM. Clinical manifestations, relevant immunologic testing, inheritance pattern, molecular diagnosis, presumed pathogenesis, and OMIM number, when annotated are compiled. Accepted therapeutic options, when available, are reviewed for each condition discussed.

CGRA5: IMMUNODEFICIENCY WITH RING CHROMOSOME 21

Ring chromosome 21 is a rare complex chromosomal deletion syndrome presenting with a variable phenotype which can include failure to thrive, hypotonia, craniofacial abnormalities, and cognitive impairment. Rare patients demonstrate hypogammaglobulinemia, potentially due to loss of a gene within the deleted segment. We report a child with ring chromosome 21 presenting with many of the associated syndromic features. This case also demonstrates panhypogammaglobulinaemia and impaired T cell function, presenting with recurrent purulent otitis media and fungal infections of the skin and renal tract. Chromosomal studies revealed 46 XX r21; 45 XX −21 mosaicism with 37% of cells containing ring chromosome 21 and the remainder being monosomy 21. She had very low IgG, absent IgA and IgE and variable IgM and a low B cell count of 6%, with no memory B cells. She had a persistent leucocytosis with a predominance of eosinophils and monocytes and an abnormal PHA. Hypogammaglobulinaemia with Ring Chromosome 21 has been previously seen in single case reports. Susceptibility to fungal infection with reduced T cell function has not been previously reported to be associated with this condition. Loss of genetic material due to formation of the ring chromosome does not include genes implicated in other defined monogenic immunodeficiencies, indicating that Ring Chromosome 21 may be an independent cause of an immunodeficiency syndrome.

Epidermodysplasia verruciformis as a manifestation of ARTEMIS deficiency in a young adult

Abstract This study is the first to report epidermodysplasia verruciformis (EV) associated with ARTEMIS deficiency in a young adult. This broadens the clinical scope of ARTEMIS deficiency, and provides a new genetic etiology for susceptibility to EV.

IgA directly inhibits antigen-dependent B cell activation following distinctive distribution of the antigen in mice

Context: Serum IgA suppresses immune responses when exposed to antigens recognized by the antibody; however, the underlying mechanism remains unclear.Objective: We herein clarified the relationships between changes in antigen distribution and antigen-dependent B cell activation in the presence or absence of IgA against the antigen in mice.Materials and methods: DBA/1J and HR-1 mice were intravenously injected with ovalbumin (OVA) and anti-OVA monoclonal IgA OA-4. The distribution of the antigen and B cell responses were measured.Results: B cell activation by injected OVA, namely, increases in anti-OVA IgG production and the populations of B220+GL7+ and B220+CD69high splenocytes, was diminished by the co-injection of OA-4. Co-injected OA-4 increased OVA in the serum as well as in the bile and gut. This was coincident with its decrease in the urine due to the inhibition of OVA monomer secretion through the formation of immune complexes. The apparent similarities in the association between fluorescein isothiocyanate (FITC)-OVA and splenic B cells in the presence and absence of OA-4 in vivo appeared to be attributed to compensation between the two effects of OA-4; an increase in serum OVA in vivo and inhibition of the association between OVA and B cells, as suggested by in vitro experiments.Discussion: Based on these results, the stimulation of B cells by OVA may be directly reduced, at least partly, by the neutralization of OVA by OA-4.Conclusion: IgA may be an effective drug for the treatment of immune disorders due to its ability to blunt antigen-specific B cell activation.

Ataxia Telangiectasia Presenting with Absent IgG, IgA, and Elevated IgM

Ataxia Telangiectasia Presenting with Absent IgG, IgA, and Elevated IgM

A novel disease-causing CD40L mutation reduces expression of CD40 ligand, but preserves CD40 binding capacity

Mutations in CD40 ligand (CD40L) that permit residual CD40L expression typically impair binding of CD40. We report a male patient who presented with recurrent bacterial respiratory tract infections, normal IgM, decreased IgG, absent IgA levels, and CD40L expression at ~50% of the level observed in the normal control. He subsequently developed autoimmunity, inflammatory bowel disease, severe opportunistic infections suggestive of a combined immunodeficiency, and a cervical spine schwannoma. Whole exome sequencing of the patient's genomic DNA revealed a novel missense mutation (p.H47Y) in CD40L. Although this mutation was predicted to be benign in silico, flow cytometry at 13 years of age demonstrated markedly decreased CD40L expression (~32% of normal control) that retained the capacity to bind soluble CD40-Ig, suggesting that the mutation impairs CD40L surface expression without affecting its affinity for CD40. This case highlights the variability in the clinical evolution and phenotype of CD40L deficiency.

Type І Hyper IgM Syndrome with Novel Mutation from India

Hyper IgM syndrome is a primary immunodeficiency disorder characterized by normal or raised levels of immunoglobulin (Ig) M with low or absent IgG, IgA, and IgE. Five genetic causes of Hyper IgM have been identified. CD40L is deficient on T cells in Type І Hyper IgM, leading to defective interaction between T and B lymphocytes and consequently an inability to switch from production of IgM to other classes of antibodies. This manuscript reports a patient with X linked Hyper IgM (XHIGM) syndrome caused by a novel mutation in the CD40 Ligand (CD40L) gene and a favorable outcome after bone marrow transplantation.

Advances in basic and clinical immunology in 2012

Basic and clinical immunology articles published in the Journal in 2012 were mostly related to the expanding area of primary immunodeficiencies (PIDs). Novel forms of PID were identified by using whole-exome sequencing or after careful examination of flow cytometric data, as in the reports of lymphocyte-specific protein tyrosine kinase, CD27, and CD21 deficiencies. Absent IgG and IgA memory B cells were described in patients with hyper-IgE syndrome, which is consistent with defective antibody response and suggests a potential benefit of immunoglobulin replacement. Impaired production of antibodies to polysaccharide antigens by the human B-cell subset analog to murine B-1 cells was reported in a child with selective polysaccharide antibody deficiency. Increased production of inflammatory cytokines by monocyte-derived cells on Toll-like receptor activation was reported in patients with X-linked agammaglobulinemia, underscoring the important role of Bruton tyrosine kinase in modulation of inflammation. The mechanisms explaining susceptibility to yeast infections and development of chronic mucocutaneous candidiasis were extensively studied. Universal newborn screening for T-cell deficiencies is being implemented in several states, resulting in the diagnosis of a higher number of immunodeficient newborns than previously estimated. The use of laboratory testing to distinguish PIDs from HIV infection was clarified. In the management of PIDs, refinement of indication and strategies to hematopoietic stem cell transplantation resulted in improved outcomes. The use of anti-IL-6 mAbs showed promise as an alternative treatment in patients with Schnitzler syndrome.

SKIN SARCOID-LIKE LESIONS IN CVID WITH POOR OUTCOME

Event Abstract Back to Event SKIN SARCOID-LIKE LESIONS IN CVID WITH POOR OUTCOME Roberto Paganelli1, 2*, Maria C. Turi1, Marika D'Urbano2, Alessia Paganelli1, 2 and Eleonora Celletti1 1 Università G. d'Annunzio of Chieti-Pescara, Medicine and Sciences of aging, Italy 2 Center for Sciences of Aging, Biogerontology and Cytokines, Italy Common variable immunodeficiency (CVID) is a heterogenous immunodeficiency disorder characterized by different clinical presentations. In about 10% of cases they present with granulomatous lesions occurring in spleen, lymphnodes, liver, lungs, skin or conjunctiva. Most patients belong to group-I CVID classification, either with B cells<1% or absent CD21low. The histopathology is similar to sarcoidosis, but its association with CVID occurs in a limited percentage of cases. We describe a CVID case, female aged 56yrs observed in November, 2009, but with clinical history dating from before 1988, with recurrent sinopulmonary infections, chronic diarrhea, low IgG (403 mg/dl) with absent IgA and IgM, treated since 2004 with IVIgs (20g every 2 months); she was diagnosed with cutaneous sarcoidosis in 2006 after a biopsy of a lesion on the left leg. Cutaneous granulomatous lesions appeared soon after in the periocular and perioral regions of the face and in both legs. Calcium levels, ACE, G6PDH were normal, Mantoux test neg, no visceral granulomas were detected by HRTC and US. We started sc Igs which allowed reconstitution of protective levels (to 686 mg/dL serum IgG), and treatments (HCQ, steroids and dapsone) unsuccessful for cutaneous and sinopulmonary new lesions suggesting sarcoidosis. An ocular CMV infection developed, leading to severely impaired sight, lip basal carcinoma and granulomatous lesions of the tongue. Leukopenia was constantly present, with 23% lymphocytes, 88% CD3+, 34% CD4+, 1,3% total and no memory switched B cells. Malignant lymphoma developed late in 2012. Management of this CVID subgroup is difficult and controversial. Keywords: CVID, Sarcoidosis, Skin Diseases, Granuloma, IVIg, Lymphoma, Non-Hodgkin, memory B cells Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Immune-mediated disease pathogenesis Citation: Paganelli R, Turi MC, D'Urbano M, Paganelli A and Celletti E (2013). SKIN SARCOID-LIKE LESIONS IN CVID WITH POOR OUTCOME. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.01065 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 28 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Prof. Roberto Paganelli, Università G. d'Annunzio of Chieti-Pescara, Medicine and Sciences of aging, Chieti scalo, Chieti, 66013, Italy, roberto.paganelli2@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Roberto Paganelli Maria C Turi Marika D'Urbano Alessia Paganelli Eleonora Celletti Google Roberto Paganelli Maria C Turi Marika D'Urbano Alessia Paganelli Eleonora Celletti Google Scholar Roberto Paganelli Maria C Turi Marika D'Urbano Alessia Paganelli Eleonora Celletti PubMed Roberto Paganelli Maria C Turi Marika D'Urbano Alessia Paganelli Eleonora Celletti Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Compromised Intestinal Epithelial Barrier Induces Adaptive Immune Compensation that Protects from Colitis

Mice lacking junctional adhesion molecule A (JAM-A, encoded by F11r) exhibit enhanced intestinal epithelial permeability, bacterial translocation, and elevated colonic lymphocyte numbers, yet do not develop colitis. To investigate the contribution of adaptive immune compensation in response to increased intestinal epithelial permeability, we examined the susceptibility of F11r(-/-)Rag1(-/-) mice to acute colitis. Although negligible contributions of adaptive immunity in F11r(+/+)Rag1(-/-) mice were observed, F11r(-/-)Rag1(-/-) mice exhibited increased microflora-dependent colitis. Elimination of Tcell subsets and cytokine analyses revealed a protective role for TGF-β-producing CD4(+) Tcells in F11r(-/-) mice. Additionally, loss of JAM-A resulted in elevated mucosal and serum IgA that was dependent upon CD4(+) Tcells and TGF-β. Absence of IgA in F11r(+/+)Igha(-/-) mice did not affect disease, whereas F11r(-/-)Igha(-/-) mice displayed markedly increased susceptibility to acute injury-induced colitis. These data establish a role for adaptive immune-mediated protection from acute colitis under conditions of intestinal epithelial barrier compromise.

Different molecular behavior of CD40 mutants causing hyper-IgM syndrome

AbstractCD40/CD40 ligand (CD40L) cross-talk plays a key role in B-cell terminal maturation in the germinal centers. Genetic defects affecting CD40 cause a rare form of hyper-immunoglobulin M (IgM) syndrome, a disorder characterized by low or absent serum IgG and IgA, associated with recurrent infections. We previously reported on a few patients with homozygous CD40 mutations resulting in lack or severe reduction of CD40 cell surface expression. Here we characterize the 3 CD40 mutants due to missense mutations or small in-frame deletions, and show that the mutated proteins are synthesized but retained in the endoplasmic reticulum (ER), likely due to protein misfolding. Interestingly, the intracellular behavior and fate differ significantly among the mutants: progressive accumulation of the P2 mutant causes endoplasmic reticulum stress and the activation of an unfolded protein response; the mutant P4 is rather efficiently disposed by the ER-associated degradation pathway, while the P5 mutant partially negotiates transport to the plasma membrane, and is competent for CD40L binding. Interestingly, this latter mutant activates downstream signaling elements when overexpressed in transfected cells. These results give new important insights into the molecular pathogenesis of HIGM disease, and suggest that CD40 deficiency can also be regarded as an ER-storage disease.