12 research outputs found
Human Secretory IgM Emerges from Plasma Cells Clonally Related to Gut Memory B Cells and Targets Highly Diverse Commensals
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. 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.</p
Human Secretory IgM Emerges from Plasma Cells Clonally Related to Gut Memory B Cells and Targets Highly Diverse Commensals
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. 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.</p
IMPACT-Global Hip Fracture Audit: Nosocomial infection, risk prediction and prognostication, minimum reporting standards and global collaborative audit. Lessons from an international multicentre study of 7,090 patients conducted in 14 nations during the COVID-19 pandemic
Estudi immunohistoquÃmic de les proteïnes reparadores de l’ADN MSH2, MSH6, MLH1 i PMS2 en cà ncer de pròstata
El paper desenvolupat per les proteïnes reparadores de l’ADN (MSH2, MSH6, MLH1 i PMS2) ha esdevingut rellevant aquests darrers anys per la seva implicació en la immunoterà pia. Tanmateix, el seu rol en cà ncer de pròstata (CaPr) està poc definit a la literatura, amb escassos estudis que reportin alteracions concretes fora de l’espectre de la SÃndrome de Lynch. Els objectius del present estudi van ser (1) analitzar l’expressió immunohistoquÃmica (IHQ) de MSH2, MSH6, MLH1, PMS2, ERG i PTEN en mostres de CaPr i conèixer la freqüència de les seves alteracions, (2) investigar la possible relació entre l’expressió proteica i la variable pronòstica Grau Grup (GG) (OMS 2016), (3) investigar la interacció entre l’expressió de les proteïnes reparadores i la d’ERG i PTEN, proteïnes codificades per gens pertanyents a la via de les translocacions, per tractar d’inferir si es tracta d’events que formin part d’una mateixa via carcinogenètica, i (4) analitzar si existeix relació entre les alteracions d’aquestes molècules i la supervivència dels pacients. A l’estudi es van incloure retrospectivament mostres de 228 pacients amb CaPr, corresponents al moment de la intervenció quirúrgica (prostatectomia radical). Es van seleccionar à rees representatives de tumor per construir 9 TMAs. Finalment, es va realitzar l’estudi d’IHQ i quantificar l’expressió de les diferents proteïnes aplicant diversos mètodes.
Respecte als resultats, les alteracions de MSH2, MLH1 i PMS2 en CaPr es van manifestar com a pèrdua d’expressió, mentre que MSH6 s’associava amb un increment d’expressió. La pèrdua IHQ de MSH2, MLH1 i PMS2 va ser un event relativament infreqüent a la nostra sèrie, en canvi, per MSH6 es van aplicar els conceptes de nivells basals i fenotip de sobreexpressió als resultats obtinguts i ambdós parà metres van ser events freqüents. Respecte al segon objectiu, l’expressió IHQ de MSH2, MSH6, MLH1 i PMS2 no va mostrar una relació estadÃsticament significativa amb la variable GG, però considerant l’agrupació de GG en dues categories GG1-4 i GG5, la sobreexpressió de MSH6 va presentar una associació estadÃsticament significativa amb els tumors prostà tics més agressius (GG5) (p=0.0281). Es va observar també una relació estadÃsticament significativa entre els tumors amb pèrdua de MSH2 i els tumors ERG-negatius (p=0.024), aixà com entre els tumors amb pèrdua de MLH1, sola o combinada amb MSH2, i els tumors ERG-negatius (p=0.019). En canvi, la pèrdua de PTEN no va mostrar una tendència estadÃsticament significativa amb les alteracions en l’expressió de MSH2, MSH6 i MLH1, i no defineix per si sola una via de carcinogènesi prostà tica com en el cas d’ERG. El temps de supervivència lliure de recurrència va ser menor en pacients amb pèrdua de PMS2, malgrat que caldria confirmar aquest resultat en una sèrie més llarga de casos amb pèrdua de PMS2.
En conclusió, és possible que la sobreexpressió de MSH6 tingui un paper reparador i podria ser un marcador de dany genòmic i d’agressivitat en CaPr, tot i que els mecanismes que controlen la seva expressió entre els diferents GG pronòstics requereixen d’estudis moleculars addicionals. Plantegem la possibilitat de que els tumors amb pèrdua de MSH2 o pèrdua de MSH2 i/o MLH1 segueixin una via carcinogenètica alternativa del CaPr, no associada a fusions genètiques, amb major freqüència de mutacions esporà diques múltiples i major potencial agressiu. Per últim, l’anà lisi IHQ de les proteïnes reparadores de l’ADN conjuntament amb l’estudi d’ERG i PTEN podria ajudar a identificar subgrups de CaPr amb diferents vies carcinogenètiques alterades i a millorar l’estratificació i maneig dels pacients. L’estudi IHQ conjunt de MSH2, MSH6, MLH1, PMS2, ERG i PTEN constitueix una eina prà ctica, reproduïble i suficientment precisa per a la seva incorporació als protocols assistencials dels serveis de Patologia.The role of Mismatch Repair Proteins (MMRP) (MSH2, MSH6, MLH1 and PMS2) has become particularly outstanding the last few years because of its implication in immunotherapy. However, its role in prostate cancer (PrCa) is less well-defined, with limited studies in the literature reporting definite alterations out of the Lynch Syndrome spectrum. The aims of the study were (1) to analyse by immunohistochemistry (IHC) the expression of MSH2, MSH6, MLH1, PMS2, ERG and PTEN and the frequency of their alterations in a cohort of PrCa samples, (2) to investigate the possible relationship between the protein expression and the Grade Group (GG) prognostic variable (WHO 2016), (3) to investigate the interaction between the MMRP expression and the one shown by ERG and PTEN, proteins which are codified by gens that belong to the rearrangement pathway, with the purpose of inferring whether they are or not phenomenon of the same carcinogenetic pathway, and (4) to analyse if there is a relation between alterations of these molecules and the survival of patients. 228 prostate tumours obtained from wholly mapped, formalin-fixed, paraffin-embedded radical prostatectomy specimens were retrospectively included in the study. A total of 9 tissue microarrays were constructed. Finally, the immunohistochemical study was performed and the expression of all the proteins was scored by different quantification methods.
Regarding to the results, MSH2, MLH1 and PMS2 alterations in PrCa were shown as loss of expression, while MSH6 alterations were associated with an increase of expression. Loss of MSH2, MLH1 and PMS2 were relatively infrequent in our series. However, based on the obtained MSH6 immunohistochemical results, we defined the concepts of basal levels and overexpressing phenotype, and both parameters presented as frequent events. With regard to the aim (2), expression of MSH2, MSH6, MLH1 and PMS2 by IHC did not show statistical differences with GG, but as the percentages of MSH6 protein overexpression were very similar in GG1 through 4, we clustered them together and compared with GG5, and MSH6 overexpression showed a statistical association with the most aggressive tumours (GG5) (p=0.0281). We also observed a statistically significant relationship between tumours with MSH2 loss and ERG-negative tumours (p=0.024), as well as between tumours with MLH1 loss, single or combined with MSH2 loss, and the ERG-negative tumours (p=0.019). Nonetheless, PTEN loss did not present significant differences with alterations in expression of MSH2, MSH6 and MLH1, and did not define by itself a carcinogenetic pathway as it occurs with ERG. Finally, despite the loss of PMS2 expression was a very infrequent event, there was a statistical association with a shorter PSA recurrence, though this result should be confirmed in a large series of cases with PMS2 loss.
In conclusion, it is possible that MSH6 overexpression displays a repairer role and could be a marker for genomic damage and aggressiveness in PrCa, even though the mechanisms controlling its variable expression between the different GG categories require additional molecular studies. We suggest the existence of an alternative non-ERG pathway associated with tumours with MSH2 loss or combined MSH2 and/or MLH1 loss, which is not linked to genetic rearrangements, and that probably presents a higher frequency of multiple sporadic mutations and a higher aggressive potential. Finally, the combined immunohistochemical analysis of MMRP, ERG and PTEN could help to identify PrCa subgroups with alterations in different carcinogenetic pathways, and to improve patient stratification and management. This combined study (MSH2, MSH6, MLH1, PMS2, ERG and PTEN) constitutes a practical, reproducible and sufficiently accurate tool for its applicability in the clinical practice and protocols of pathology departments
Estudi immunohistoquÃmic de les proteïnes reparadores de l'ADN MSH2, MSH6, MLH1 i PMS2 en cà ncer de pròstata
El paper desenvolupat per les proteïnes reparadores de l'ADN (MSH2, MSH6, MLH1 i PMS2) ha esdevingut rellevant aquests darrers anys per la seva implicació en la immunoterà pia. Tanmateix, el seu rol en cà ncer de pròstata (CaPr) està poc definit a la literatura, amb escassos estudis que reportin alteracions concretes fora de l'espectre de la SÃndrome de Lynch. Els objectius del present estudi van ser (1) analitzar l'expressió immunohistoquÃmica (IHQ) de MSH2, MSH6, MLH1, PMS2, ERG i PTEN en mostres de CaPr i conèixer la freqüència de les seves alteracions, (2) investigar la possible relació entre l'expressió proteica i la variable pronòstica Grau Grup (GG) (OMS 2016), (3) investigar la interacció entre l'expressió de les proteïnes reparadores i la d'ERG i PTEN, proteïnes codificades per gens pertanyents a la via de les translocacions, per tractar d'inferir si es tracta d'events que formin part d'una mateixa via carcinogenètica, i (4) analitzar si existeix relació entre les alteracions d'aquestes molècules i la supervivència dels pacients. A l'estudi es van incloure retrospectivament mostres de 228 pacients amb CaPr, corresponents al moment de la intervenció quirúrgica (prostatectomia radical). Es van seleccionar à rees representatives de tumor per construir 9 TMAs. Finalment, es va realitzar l'estudi d'IHQ i quantificar l'expressió de les diferents proteïnes aplicant diversos mètodes. Respecte als resultats, les alteracions de MSH2, MLH1 i PMS2 en CaPr es van manifestar com a pèrdua d'expressió, mentre que MSH6 s'associava amb un increment d'expressió. La pèrdua IHQ de MSH2, MLH1 i PMS2 va ser un event relativament infreqüent a la nostra sèrie, en canvi, per MSH6 es van aplicar els conceptes de nivells basals i fenotip de sobreexpressió als resultats obtinguts i ambdós parà metres van ser events freqüents. Respecte al segon objectiu, l'expressió IHQ de MSH2, MSH6, MLH1 i PMS2 no va mostrar una relació estadÃsticament significativa amb la variable GG, però considerant l'agrupació de GG en dues categories GG1-4 i GG5, la sobreexpressió de MSH6 va presentar una associació estadÃsticament significativa amb els tumors prostà tics més agressius (GG5) (p=0.0281). Es va observar també una relació estadÃsticament significativa entre els tumors amb pèrdua de MSH2 i els tumors ERG-negatius (p=0.024), aixà com entre els tumors amb pèrdua de MLH1, sola o combinada amb MSH2, i els tumors ERG-negatius (p=0.019). En canvi, la pèrdua de PTEN no va mostrar una tendència estadÃsticament significativa amb les alteracions en l'expressió de MSH2, MSH6 i MLH1, i no defineix per si sola una via de carcinogènesi prostà tica com en el cas d'ERG. El temps de supervivència lliure de recurrència va ser menor en pacients amb pèrdua de PMS2, malgrat que caldria confirmar aquest resultat en una sèrie més llarga de casos amb pèrdua de PMS2. En conclusió, és possible que la sobreexpressió de MSH6 tingui un paper reparador i podria ser un marcador de dany genòmic i d'agressivitat en CaPr, tot i que els mecanismes que controlen la seva expressió entre els diferents GG pronòstics requereixen d'estudis moleculars addicionals. Plantegem la possibilitat de que els tumors amb pèrdua de MSH2 o pèrdua de MSH2 i/o MLH1 segueixin una via carcinogenètica alternativa del CaPr, no associada a fusions genètiques, amb major freqüència de mutacions esporà diques múltiples i major potencial agressiu. Per últim, l'anà lisi IHQ de les proteïnes reparadores de l'ADN conjuntament amb l'estudi d'ERG i PTEN podria ajudar a identificar subgrups de CaPr amb diferents vies carcinogenètiques alterades i a millorar l'estratificació i maneig dels pacients. L'estudi IHQ conjunt de MSH2, MSH6, MLH1, PMS2, ERG i PTEN constitueix una eina prà ctica, reproduïble i suficientment precisa per a la seva incorporació als protocols assistencials dels serveis de Patologia.The role of Mismatch Repair Proteins (MMRP) (MSH2, MSH6, MLH1 and PMS2) has become particularly outstanding the last few years because of its implication in immunotherapy. However, its role in prostate cancer (PrCa) is less well-defined, with limited studies in the literature reporting definite alterations out of the Lynch Syndrome spectrum. The aims of the study were (1) to analyse by immunohistochemistry (IHC) the expression of MSH2, MSH6, MLH1, PMS2, ERG and PTEN and the frequency of their alterations in a cohort of PrCa samples, (2) to investigate the possible relationship between the protein expression and the Grade Group (GG) prognostic variable (WHO 2016), (3) to investigate the interaction between the MMRP expression and the one shown by ERG and PTEN, proteins which are codified by gens that belong to the rearrangement pathway, with the purpose of inferring whether they are or not phenomenon of the same carcinogenetic pathway, and (4) to analyse if there is a relation between alterations of these molecules and the survival of patients. 228 prostate tumours obtained from wholly mapped, formalin-fixed, paraffin-embedded radical prostatectomy specimens were retrospectively included in the study. A total of 9 tissue microarrays were constructed. Finally, the immunohistochemical study was performed and the expression of all the proteins was scored by different quantification methods. Regarding to the results, MSH2, MLH1 and PMS2 alterations in PrCa were shown as loss of expression, while MSH6 alterations were associated with an increase of expression. Loss of MSH2, MLH1 and PMS2 were relatively infrequent in our series. However, based on the obtained MSH6 immunohistochemical results, we defined the concepts of basal levels and overexpressing phenotype, and both parameters presented as frequent events. With regard to the aim (2), expression of MSH2, MSH6, MLH1 and PMS2 by IHC did not show statistical differences with GG, but as the percentages of MSH6 protein overexpression were very similar in GG1 through 4, we clustered them together and compared with GG5, and MSH6 overexpression showed a statistical association with the most aggressive tumours (GG5) (p=0.0281). We also observed a statistically significant relationship between tumours with MSH2 loss and ERG-negative tumours (p=0.024), as well as between tumours with MLH1 loss, single or combined with MSH2 loss, and the ERG-negative tumours (p=0.019). Nonetheless, PTEN loss did not present significant differences with alterations in expression of MSH2, MSH6 and MLH1, and did not define by itself a carcinogenetic pathway as it occurs with ERG. Finally, despite the loss of PMS2 expression was a very infrequent event, there was a statistical association with a shorter PSA recurrence, though this result should be confirmed in a large series of cases with PMS2 loss. In conclusion, it is possible that MSH6 overexpression displays a repairer role and could be a marker for genomic damage and aggressiveness in PrCa, even though the mechanisms controlling its variable expression between the different GG categories require additional molecular studies. We suggest the existence of an alternative non-ERG pathway associated with tumours with MSH2 loss or combined MSH2 and/or MLH1 loss, which is not linked to genetic rearrangements, and that probably presents a higher frequency of multiple sporadic mutations and a higher aggressive potential. Finally, the combined immunohistochemical analysis of MMRP, ERG and PTEN could help to identify PrCa subgroups with alterations in different carcinogenetic pathways, and to improve patient stratification and management. This combined study (MSH2, MSH6, MLH1, PMS2, ERG and PTEN) constitutes a practical, reproducible and sufficiently accurate tool for its applicability in the clinical practice and protocols of pathology departments
Persistent cutaneous abdominal ulcerations secondary to diffuse dermal angiomatosis: an underestimated sign for severe atherosclerosis: A case report.
BACKGROUND: Diffuse dermal angiomatosis (DDA) is a rare, acquired, reactive vascular proliferation, clinically characterized by livedoid erythematous-violaceous plaques, which frequently evolve to ulceration and necrosis. Histopathologically, it is manifested by a diffuse proliferation of endothelial cells within the full thickness of the dermis. DDA has been mainly associated with severe peripheral atherosclerosis. METHODS: We report a 63-year-old woman who presented with multiple erythematous-violaceous plaques with central deep skin ulcers on thighs, lower abdomen, and perianal area, associated with intermittent claudication, low-grade fever, and weight loss. Initially, the clinical picture along with positive cultures for Klebsiella pneumoniae suggested a multifocal ecthyma gangrenosum; nevertheless, a skin biopsy showed a diffuse dermal proliferation of endothelial cells interstitially arranged between collagen bundles. A computed tomography scan revealed severe aortic atheromatosis with complete luminal occlusion of the infrarenal aorta and common iliac arteries. RESULTS: The diagnosis of DDA secondary to severe atherosclerosis was established. The patient underwent a left axillofemoral bypass surgery with a rapidly healing of the ulcers in the next weeks./nCONCLUSIONS: DDA should be considered in the differential diagnosis of livedoid ischemic lesions. Recognition of DDA as a cutaneous sign of severe peripheral vascular disease is important for both dermatologists and internists. Recognition of risk factors and their management with an early intervention to correct tissue ischemia can be curative
SARS-CoV-2 identified by transmission electron microscopy in lymphoproliferative and ischaemic intestinal lesions of COVID-19 patients with acute abdominal pain: two case reports
Background: SARS-CoV-2 may produce intestinal symptoms that are generally mild, with a small percentage of patients developing more severe symptoms. The involvement of SARS-CoV-2 in the physiopathology of bowel damage is poorly known. Transmission electron microscopy (TEM) is a useful tool that provides an understanding of SARS-CoV-2 invasiveness, replication and dissemination in body cells but information outside the respiratory tract is very limited. We report two cases of severe intestinal complications (intestinal lymphoma and ischaemic colitis) in which the presence of SARS-CoV-2 in intestinal tissue was confirmed by TEM. These are the first two cases reported in the literature of persistence of SARS-CoV-2 demonstrated by TEM in intestinal tissue after COVID 19 recovery and SARS-CoV-2 nasopharyngeal clearance. Case presentation: During the first pandemic peak (1st March-30th April 2020) 932 patients were admitted in Hospital Universitari Mútua Terrassa due to COVID-19, 41 (4.4%) required cross-sectional imaging techniques to assess severe abdominal pain and six of them (0.64%) required surgical resection. SARS-CoV-2 in bowel tissue was demonstrated by TEM in two of these patients. The first case presented as an ileocaecal inflammatory mass which turned to be a B-cell lymphoma. Viral particles were found in the cytoplasm of endothelial cells of damaged mucosa. In situ hybridization was negative in tumour cells, thus ruling out an oncogenic role for the virus. SARS-CoV-2 remained in intestinal tissue 6 months after nasopharyngeal clearance, suggesting latent infection. The second patient had a severe ischaemic colitis with perforation and SARS-CoV-2 was also identified in endothelial cells. Conclusions: Severe intestinal complications associated with COVID-19 are uncommon. SARS-CoV-2 was identified by TEM in two cases, suggesting a causal role in bowel damage
ERG overexpression plus SLC45A3 (prostein) and PTEN expression loss: Strong association of the triple hit phenotype with an aggressive pathway of prostate cancer progression
TMPRSS2 and SLC45A3 rearrangements may coexist in the same tumor. ERG rearrangements and PTEN loss are concomitant events in prostate cancer (PrCa), and can cooperate in progression. We have reported that mRNA expression of TMPRSS2-ERG and SLC45A3-ERG rearrangements plus PTEN loss define an aggressive tumor subset. The aim of this study has been to validate these results by immunohistochemistry in a large cohort of tumors. ERG, SLC45A3 and PTEN immunostaining and their association with pathological features and PSA progression-free survival were analyzed in 220 PrCa (PSMAR-Biobank, Barcelona, Spain). ERG protein expression was found in 46.8% and SLC45A3 and PTEN loss in 30% and 34% tumors, respectively. Single ERG positive immunostaining was associated with GS = 6 tumors (p = 0.016), double ERG+/PTEN loss with GS = 7 (p = 0.008) and Grade Group 2 (GG) or GG3 cases (p = 0.042), ERG+/SLC45A3 loss/PTEN loss ("triple hit") with GS ≥ 8 (p < 0.0001) and GG4 or GG5 tumors (p = 0.0003). None of GS = 6 nor = GG1 cases showed this combination. In the GS ≥ 8 group, ERG+ (p = 0.002), PTEN loss (p = 0.009) and "triple hit" (p = 0.003) were associated with Gleason pattern 3 component, and single SLC45A3 loss (p = 0.036) with GS ≥ 8 without pattern 3. The number of aberrant events and the triple hit were strongly associated with shorter PSA progression-free survival. In GS = 6 PrCa, single ERG+ was also associated with progression. ERG+ identifies a distinct pathway of PrCa. Additional assessment of PTEN and SLC45A3 adds relevant prognostic information. The triple hit phenotype (ERG+/SLC45A3 loss/PTEN loss) is associated with progression and could be used for patient stratification, treatment and follow-up
Human Secretory IgM Emerges from Plasma Cells Clonally Related to Gut Memory B Cells and Targets Highly Diverse Commensals
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.Supported by European Advanced Grant (ERC-2011-ADG-20110310), MINECO (SAF2014-52483-R), AGAUR (2014 SGR 832), US NIH grants P01 AI61093, R01 AI57653, and U01 AI95613 (to A.C.), Boeringher Ingelheim grant 134564-2 (to A.C.), NIH grant R01 DK 112296-01 (to A.C. and S.M.), and Fondo de Investigación Sanitaria ISCIII fellowships CD14/00060 and CM13/00136 (to G.M. and L.C., respectively)
Human Secretory IgM Emerges from Plasma Cells Clonally Related to Gut Memory B Cells and Targets Highly Diverse Commensals
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.Supported by European Advanced Grant (ERC-2011-ADG-20110310), MINECO (SAF2014-52483-R), AGAUR (2014 SGR 832), US NIH grants P01 AI61093, R01 AI57653, and U01 AI95613 (to A.C.), Boeringher Ingelheim grant 134564-2 (to A.C.), NIH grant R01 DK 112296-01 (to A.C. and S.M.), and Fondo de Investigación Sanitaria ISCIII fellowships CD14/00060 and CM13/00136 (to G.M. and L.C., respectively)