Summary
Background
Butyrate, propionate and acetate are short chain fatty acids (SCFA), important for maintaining a healthy colon and are considered as protective in colorectal carcinogenesis. ...However, they may also regulate immune responses and the composition of the intestinal microbiota. Consequently, their importance in a variety of chronic inflammatory diseases is emerging.
Aims
To review the physiology and metabolism of SCFA in humans, cellular and molecular mechanisms by which SCFA may act in health and disease, and approaches for therapeutic delivery of SCFA.
Methods
A PubMed literature search was conducted for clinical and pre‐clinical studies using search terms: ‘dietary fibre’, short‐chain fatty acids’, ‘acetate’, ‘propionate’, ‘butyrate’, ‘inflammation’, ‘immune’, ‘gastrointestinal’, ‘metabolism’.
Results
A wide range of pre‐clinical evidence supports roles for SCFA as modulators of not only colonic function, but also multiple inflammatory and metabolic processes. SCFA are implicated in many autoimmune, allergic and metabolic diseases. However, translating effects of SCFA from animal studies to human disease is limited by physiological and dietary differences and by the challenge of delivering sufficient amounts of SCFA to the target sites that include the colon and the systemic circulation. Development of novel targeted approaches for colonic delivery, combined with postbiotic supplementation, may represent desirable strategies to achieve adequate targeted SCFA delivery.
Conclusions
There is a large array of potential disease‐modulating effects of SCFA. Adequate targeted delivery to the sites of action is the main limitation of such application. The ongoing development and evaluation of novel delivery techniques offer potential for translating promise to therapeutic benefit.
The notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated ...in healthy individuals (n=20) that the CD19-CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19-CD81+ and CD19-CD81- BMPCs. Afterwards, we demonstrated in 225 newly diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully differentiated (CD19-CD81-) clones, 38% intermediate-differentiated (CD19-CD81+) and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR: 1.7; P=0.005) and overall survival (HR: 2.1; P=0.006). Longitudinal comparison of diagnostic vs minimal-residual-disease samples (n=40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (for example: PAX5), and show distinct mutation profile vs fully differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harbouring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles.
Background
While treatment for atopic rhinitis is aimed mostly to relieve symptoms, only allergen‐specific immunotherapy (AIT) is targeted to modify the natural history of allergic diseases. This ...results in sustained clinical tolerance, even when treatment has stopped. The immunomodulatory effects of AIT are attributed mainly to increased regulatory T‐cell function and increased allergen‐specific IgG4, yet little is known about the effect on the memory B‐cell compartment.
Objective
We aimed to examine the effects of AIT on the IgE‐ and IgG subclass‐expressing memory B cells.
Methods
We recruited 29 patients with atopic seasonal rhinoconjunctivitis and performed a longitudinal analysis of the peripheral immune compartment before, during, and after sublingual immunotherapy (SLIT) for allergy to temperate grass pollen, predominantly to ryegrass pollen (RGP; Lolium perenne). Using flow cytometry on peripheral blood mononuclear cells and serum immunoassays, we analyzed the effects of a 4 months preseasonal treatment regimen comprising two or three courses in consecutive years on circulating IgE+ and IgG+ memory B cells and allergen‐specific Ig levels.
Results
SLIT increased RGP‐specific serum IgG2 and IgG4, as well as the frequencies of IgG2+ and IgG4+ memory B cells, whereas no effect was observed on the IgE+ memory B‐cell compartment. Furthermore, SLIT enhanced proportions of regulatory T cells specific to RGP. These changes were associated with clinical improvement.
Conclusion
Our data provide evidence for immunological effects of SLIT on B‐cell memory. Skewing responses toward IgG2 and IgG4 subclasses might be a mechanism to suppress IgE‐mediated allergic responses.
This study examines the effect of ryegrass pollen AIT on B‐cell responses in a population of 29 patients with allergic rhinitis. Successful immunotherapy for ryegrass pollen allergy increases allergen‐specific IgG2 and IgG4 serum levels, and proportions of IgG2‐ and IgG4‐expressing memory B cells. Skewing toward the anti‐inflammatory IgG2 and IgG4 subclasses might be a mechanism to suppress IgE‐mediated allergic responses.
Despite the critical role of soluble IgE in the pathology of IgE‐mediated allergic disease, little is known about abnormalities in the memory B cells and plasma cells that produce IgE in allergic ...patients. We here applied a flow cytometric approach to cross‐sectionally study blood IgE+ memory B cells and plasmablasts in 149 children with atopic dermatitis, food allergy, and/or asthma and correlated these to helper T(h)2 cells and eosinophils. Children with allergic disease had increased numbers of IgE+CD27‐ and IgE+CD27+ memory B cells and IgE+ plasmablasts, as well as increased numbers of eosinophils and Th2 cells. IgE+ plasmablast numbers correlated positively with Th2 cell numbers. These findings open new possibilities for diagnosis and monitoring of treatment in patients with allergic diseases.
Secretory immunoglobulin A (SIgA) enhances host-microbiota symbiosis, whereas SIgM remains poorly understood. We found that gut IgM+ plasma cells (PCs) were more abundant in humans than mice and ...clonally related to a large repertoire of memory IgM+ B cells disseminated throughout the intestine but rare in systemic lymphoid organs. In addition to sharing a gut-specific gene signature with memory IgA+ B cells, memory IgM+ B cells were related to some IgA+ clonotypes and switched to IgA in response to T cell-independent or T cell-dependent signals. These signals induced abundant IgM which, together with SIgM from clonally affiliated PCs, recognized mucus-embedded commensals. Bacteria recognized by human SIgM were dually coated by SIgA and showed increased richness and diversity compared to IgA-only-coated or uncoated bacteria. Thus, SIgM may emerge from pre-existing memory rather than newly activated naive IgM+ B cells and could help SIgA to anchor highly diverse commensal communities to mucus.
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•IgM+ PCs generating SIgM are relatively abundant in human but not mouse gut•IgM+ PCs clonally relate to a large gut repertoire of memory IgM+ B cells•Gut memory IgM+ B cells express a tissue-specific signature and can switch to IgA•Human but not mouse SIgM binds a highly diverse microbiota dually coated by SIgA
Magri et al. found that the human gut includes a large memory IgM+ B cell repertoire clonally related to plasma cells mounting SIgM responses against mucus-embedded commensals co-targeted by SIgA. Dually coated bacteria are detected in humans but not mice and show increased diversity and richness compared to SIgA-only-coated or uncoated bacteria.
Predicting human phenotypes from genotypes is a newly emerging field with relevance for personalized medicine 1 and forensics 2. However, only a few phenotypic traits can currently be identified from ...DNA information with accuracies sufficient for practical applications 1, most notably human eye (iris) color 3. It could be expected that individual age is too biologically complex to allow a simple and accurate molecular estimation from biological materials. Indeed, previously proposed genetic methods for human age estimation, based on the accumulation of mitochondrial DNA deletions or on telomere shortening, show low accuracies and various technical problems, and are therefore not suitable for practical applications 4. Proposed biochemical methods, such as those based on the accumulation of D-aspartic acid, involve the destructive analysis of specific body parts (such as bones, teeth and ligaments), and suffer from technical issues and bio-degradation 4. In the present study, we demonstrate that human individual age can be estimated accurately and reliably from blood using T-cell DNA rearrangements, and we provide a robust and sensitive real-time quantitative PCR protocol for application in various areas of bioscience.
Antibody deficiencies constitute the largest group of symptomatic primary immunodeficiency diseases. In several patients, mutations in CD19 have been found to underlie disease, demonstrating the ...critical role for the protein encoded by this gene in antibody responses; CD19 functions in a complex with CD21, CD81, and CD225 to signal with the B cell receptor upon antigen recognition. We report here a patient with severe nephropathy and profound hypogammaglobulinemia. The immunodeficiency was characterized by decreased memory B cell numbers, impaired specific antibody responses, and an absence of CD19 expression on B cells. The patient had normal CD19 alleles but carried a homozygous CD81 mutation resulting in a complete lack of CD81 expression on blood leukocytes. Retroviral transduction and glycosylation experiments on EBV-transformed B cells from the patient revealed that CD19 membrane expression critically depended on CD81. Similar to CD19-deficient patients, CD81-deficient patients had B cells that showed impaired activation upon stimulation via the B cell antigen receptor but no overt T cell subset or function defects. In this study, we present what we believe to be the first antibody deficiency syndrome caused by a mutation in the CD81 gene and consequent disruption of the CD19 complex on B cells. These findings may contribute to unraveling the genetic basis of antibody deficiency syndromes and the nonredundant functions of CD81 in humans.
Patients with hypogammaglobulinemia who do not fulfill all the classical diagnostic criteria for common variable immunodeficiency (reduction of two immunoglobulin isotypes and a reduced response to ...vaccination) constitute a diagnostic and therapeutic dilemma, because information concerning the clinical and immunological characteristics of these patients with idiopathic primary hypogammaglobulinemia is not available. In 44 common variable immunodeficiency and 21 idiopathic primary hypogammaglobulinemia patients we determined the clinical phenotypes and performed flow cytometric immunophenotyping to assess the pathophysiological B-cell patterns and memory B-cell subset counts. Age-matched B-cell subset reference values of 130 healthy donors were generated. Severe pneumonia and bronchiectasis occurred at similar frequencies in idiopathic primary hypogammaglobulinemia and common variable immunodeficiency. Although IgG levels were only moderately reduced compared to common variable immunodeficiency, 12 of 21 idiopathic primary hypogammaglobulinemia patients required immunoglobulin replacement. Non-infectious disease-related clinical phenotypes (autoimmune cytopenia, polyclonal lymphocytic proliferation and persistent unexplained enteropathy) were exclusively observed in common variable immunodeficiency and were associated with early peripheral B-cell maturation defects or B-cell survival defects. T-cell dependent memory B-cell formation was more severely affected in common variable immunodeficiency. Furthermore, 14 of 21 idiopathic primary hypogammaglobulinemia patients showed normal peripheral B-cell subset counts, suggestive for a plasma cell defect. In conclusion, idiopathic primary hypogammaglobulinemia patients who do not fulfill all diagnostic criteria of common variable immunodeficiency have moderately decreased immunoglobulin levels and often a normal peripheral B-cell subset distribution, but still suffer from serious infectious complications.
B-cell depletion can improve a variety of chronic inflammatory diseases, but does not appear beneficial for patients with Crohn's disease.
To elucidate the involvement of B cells in Crohn's disease, ...we here performed an 'in depth' analysis of intestinal and blood B-cells in this chronic inflammatory disease.
Patients with Crohn's disease were recruited to study B-cell infiltrates in intestinal biopsies (n = 5), serum immunoglobulin levels and the phenotype and molecular characteristics of blood B-cell subsets (n = 21). The effects of infliximab treatment were studied in 9 patients.
Granulomatous tissue showed infiltrates of B lymphocytes rather than Ig-secreting plasma cells. Circulating transitional B cells and CD21low B cells were elevated. IgM memory B cells were reduced and natural effector cells showed decreased replication histories and somatic hypermutation (SHM) levels. In contrast, IgG and IgA memory B cells were normally present and their Ig gene transcripts carried increased SHM levels. The numbers of transitional and natural effector cells were normal in patients who responded clinically well to infliximab.
B cells in patients with Crohn's disease showed signs of chronic stimulation with localization to granulomatous tissue and increased molecular maturation of IgA and IgG. Therapy with TNFα-blockers restored the defect in IgM memory B-cell generation and normalized transitional B-cell levels, making these subsets candidate markers for treatment monitoring. Together, these results suggest a chronic, aberrant B-cell response in patients with Crohn's disease, which could be targeted with new therapeutics that specifically regulate B-cell function.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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