Saturday, April 14, 2018

Access to self antigens during germinal center reaction improves self/nonself discrimination against mimicry antigens

This week journal Science published short paper from Chis Goodnow's lab that raises very interesting question about biological significance for existence of anergic self-reactive B cells. Ordinarily, developing B cells when encountering self-antigens undergo deletion, receptor editing or physiological receptor signaling down-regulation that makes such 'anergic' B cells refractory to presence of normal level of self antigens. However, anergic B cells could be re-energized if challenged with high density self antigens or antigens sharing epitope similarity with self antigen.

Now, new study indicates that rather than developing into full blown auto-reactive immune response, anergic B cells when challenged with mimicry antigens mutates its receptors in a such a way, during process of hypermutation, as to achieve a high degree of discrimination between mimicry antigen and actual self antigen.   

The experimental set up itself is quite simple, only complex aspect was to analyze single cell B cell receptor mutation and their binding affinity recovered after antigen challenge. Two type of hosts were used here. Both groups harbor small numbers of self-reactive B cells (CD45.1+ SWHEL B cells)  but only one group also harbored a specific antigen detected by these transgenic SWHEL B cells and expressed "as as an integral membrane protein, mHEL3X, encoded by a transgene with a ubiquitin promoter".



As expected SWHEL B cells in double transgenic hosts were anergic with decreased surface immunoglobulin M (IgM) expression. However, these anergic B cells could be re-activated in germinal centers when challenged with Sheep red blood cells (SRBCs) covalently coupled with self antigen, HEL3X, at high density.



Next set of experiments however showed very unusual results. When challenged with mimicry antigen DEL which slightly differs from self HEL antigen anergic B cell receptors in double transgenic hosts rapidly accumulated mutations that decreased binding affinity to self HEL antigen.



In fact, single cell BCR receptor analysis clearly showed that presence of self antigens dramatically enhanced anergic B cell receptor mutations that allowed up to 5,000-fold better discrimination capacity between self and mimicry antigen (pre vs. post comparison). This is based on assumption that starting affinity to self are the same for both normal and anergic SWHEL B cells population. 




In summary, this study suggests that during germinal center reaction where B cell receptors undergo hypermutation, anergic B cell repertoire, in presence of self antigen, could be salvaged (redeemed) by accelerated accumulation of mutations that modifies their original specificity away from self antigens and allowing more fine discrimination between self and mimicry, cross-reactive nonself antigen. In this scenario, self antigens serve as negative-feedback templates that hypermutating receptors interacts repeatedly in real time to achieve minimal level of binding.

In my view such negative-feedback loop to B cells can only delivered by specialized cell type in germinal center that maintains, keeps memory of host's unadulterated "self antigen collection'' visible to B cells, a task somewhat similar to Foxp3+ Tregs. So, it is possible that new cell type need to be discovered that does it or it is also possible that the same Foxp3+ Tregs localized in germinal centers, referred as follicular Foxp3+ T regs, do it too. 

What are the global implication for such mechanism: It could explain why anergic B cells hang around and how their repertoire could be salvaged without compromising tolerance. The authors also puts forward another intriguing idea that commensal mcrobes and their antigens could serve as negative-feedback loop 'self' templates for anergic B cells that allows them to discriminate between self and mimicking nonself during immune response. 

posted by David Usharauli       



Sunday, April 1, 2018

Chronic systemic inflammation in Lupus could be driven by bacterial antigen mimicry to human autoantigen Ro60

Earlier I discussed a new study in journal Science from Martin Kriegel's lab at Yale University School of Medicine that showed how translocation of commensal bacterial species E. gallinarum could amplify autoimmune phenotype in Lupus prone mouse model. It appears that his lab had another paper under review that was published this week in Science Translation Medicine, a sister publication run by Science. In this study the authors tried to show that auto-reactivity to auto-antigen Ro60 frequently observed in lupus susceptible patients could potentially be driven and sustained by commensal microbial species [turned pathobionts] expressing Ro60-like molecules.

The authors showed that there are substantial overlap between T cell epitopes in human Ro60 and Ro60 molecule from bacterial species such as Propionibacterium propionicum (P. prop) and Bacteroides thetaiotaomicron (B. theta)




Memory T cells freshly sorted from anti-Ro60 reactive SLE (lupus) patients responded to P. prop and B. theta lysates.   



In summary, this study suggests that commensal bacterial species turned pathobionts could initiate and sustain lupus phenotype in susceptible individuals. This is not a definitive study. First, it is obvious that commensals per se cannot induce lupus but only in susceptible individuals (almost every individual carries these commensals). What exactly constitutes this susceptibility in humans to lupus [or any other autoimmune diseases] is a black box presently. Moreover, their "analysis revealed no significantly different bacterial OTUs in the fecal, oral, or skin microbiomes between anti-Ro60–positive and anti-Ro60–negative subjects". However since resolution of currently available microbiome analytical tools are quite low it is still possible that at bacterial species or strain level there maybe significant differences between healthy vs. lupus and Ro60-positive vs. Ro60-negative populations.

posted by David Usharauli


Wednesday, March 21, 2018

Live, not dead bacteria, augments human antibody response via TLR8 - T follicular helper cell axis

Immune system protects against pathogens. In natural settings, live pathogens cause diseases. So, it is very intuitive to think that immune system could have developed a specialized way to detect pathogen's "live signature". Few years back, Julie Magarian Blander's lab (former postdoctoral scientist in Ruslan Medzhitov' lab) published study showing that mRNA from live bacteria served as "live signature" they called vita-PAMP

Now, new paper in nature immunology from Leif Sander's lab (a former postdoctoral scientist in her lab and the first author of initial study) showed that in humans TLR8 may serve as a detector of vita-PAMP mRNA from live bacteria and augment antibody response. It is very nice study done primarily on ex vivo/in vitro human cells cultures (interestingly, Blander's lab also published this month new study about vita-PAMPs in mice in journal Immunity. But it is very messy and bloated study. Basically, in this case pupil outdid his [former] master).

Here the authors showed that live, replication-defective E. coli strain but not heat-inactivated dead one, could induce differentiation of human follicular helper T cells (TFH cells).



These TFH cells were functionally active inducing antibody-secreting plasmablast generation from B cells.



Live bacteria, not dead one, specifically induced IL-12p70 generation from human monocytes (unlike mouse, differentiation of human TFH cells requires IL-12p70).



Indeed, antibody blockade confirmed a major role of IL-12p70 in generation of IL-21-producing human TFH cells.



Stimulation of human monocytes with various TLR agonists showed that engagement of TLR8 (single-strand RNA sensor) with its agonist ligand (CL075 or R848) were responsible for vita-PAMP effect on IL-12p70 production.



Similar vita-PAMP effect of TLR8 signaling were seen for human IL-21-producing TFH cell generation.



In summary, this study indicates that unlike LPS-derivative MPLA or CpG fortified vaccines, inclusion of TLR8 agonists, such as CL075, could augment antibody responses. While study is well done we need to keep in mind that it is produced by members of the 'same initial' group (Blander and Sander) who first reported vita-PAMP effect. We don't have analogous studies from other labs who can independently confirm these observations

posted by David Usharauli

  

Tuesday, March 20, 2018

IL-33 is a natural target of allergen proteases

IL-33 is a member of IL-1 family and requires proteolytic cleavage to form active form. It has already been linked to allergy manifestation. Now, new study in nature immunology expands on earlier observations to show that full-length non-active IL-33 (IL-33FL) is a natural target of group of allergens with proteases activity.

In general, many known allergens display protease activity such as from fungi, mites, pollens, insects. Co-incubation of IL-33FL with such allergen proteases in presence of innate lymphoid cells type II (ILC2) generated biologically-active smaller fragments and release of type II cytokines.



IL-33FL is an intra-nuclear proto-chemokine found in epithelial and endothelial cells. So, how allergens get access to it? It requires cell damage to release IL-33FL extra-cellularly. However, it is not clear if any allergen proteases can damage cells. At least one such allergen from fungus, Alternaria alternata (A. alternata) can damage cell and then cleave IL-33FL.



Similar effects were seen in vivo using IL-33KO mice. In these mice, recruitment of eosinophils, a readout for IL-33-driven allergic response, were only observed when injected with pre-incubated IL-33FL and A. alternata mixture.




In summary, these results suggest that allergen from A. alternata with protease activity can damage cells to release IL-33FL and cleave it into biologically-active shorter peptides. However, this study did not show that other allergens can deliver similar double punch. Also, it is not clear how this innate mechanism translates to adaptive immune system to generate allergen-specific T cell and antibody responses.

posted by David Usharauli


Thursday, March 15, 2018

Reduced CTLA-4 signaling predisposes to Th2 driven gastric tumorigenesis

Anti-CTLA4 antibodies such as Yervoy, has been used in clinical practice to treat solid tumors. It supposed to work either by augmenting and revitalizing effector T cells function directly or indirectly through temporal silencing of inhibitory Foxp3+ Treg population or both. However, new study from Journal of Experimental Medicine showed that at least in [genetically predisposed] mice reduced CTLA-4 signaling by itself could cause Th2 driven tumorigenic transformation of stomach epithelial tissue.

For this study the authors created transgenic CTLA4 shRNA knockdown (CTLA4KD) mice on the BALB/c × C57BL/6 (B6) mixed genetic background. This they did because it appears that BALB/c but not B6 mice were susceptible developing gastric tumors in this model. CTLA4KD mice showed gastric epithelial transformation by 20w of age. Similarly, month long treatment of newborn BALB/c mice with anti-CTLA4 antibody also led to gastric epithelial transformation.



This tumorigenic transformation was CD4 T cell dependent and effector T cells from CTLA4KD but not from WT mice could mediate it. It indicated that changes in effector T cell composition and functionality were driving de novo inflammatory tumorigenesis.



Interestingly, gastric epithelial transformation were happening even in germ-free CTLA4KD mice lacking microbiota. However, since these mice also harbor increased numbers of inflammatory T cells, in all subsets analyzed such as Th1, Th2, Th17, and independent of microbiota it could indicate that T cells could be responding to antigens from food or environment.


Finally, elimination of canonical T helper cytokines showed that surprisingly neither IFN-γ nor IL-17 but IL-4 deficiency could abolish gastric epithelial transformation under conditions of reduced CTLA-4 activity.



In summary, this study suggests that inherited or clinically-induced reduction of CTLA-4 signaling in predisposed individuals could paradoxically lead to inflammatory tumorigenesis driven by type II immunity.

posted by David Usharauli



Saturday, March 10, 2018

Translocation of a specific gut pathobiont, Enterococcus gallinarum, exacerbate autoimmune phenotype

A new study in journal Science suggests that a specific gut pathobiont, Enterococcus gallinarum, could exacerbate autoimmune phenotype in predisposed mouse strain. This autoimmune phenotype in mice are thought to represent mouse version of human systemic lupus erythematosus (SLE).

SLE is associated with genetic polymorphism linked to excessive signaling of RNA sensing Toll-like receptor 7 (TLR7) and type I interferons (IFNs). In the specific pathogen-free (NZW × BXSB)F1 hybrid mouse, responses to endogenous retrovirus glycoprotein 70 (ERV gp70) via TLR7 signaling leads to progressive autoimmune response by pathogenic anti-phospholipid [β2-glycoprotein I (β2GPI)] and anti–double-stranded DNA (dsDNA) antibodies.

The authors observed that certain antibiotic treatment significantly improved survival of (NZW × BXSB)F1 hybrid mice.



Further experiments showed that there was bacterial translocation from gut tissue into portal veins and livers in these mice that could be reduced by antibiotic treatment.




16S rRNA sequencing and species-specific PCR consistently revealed Enterococcus gallinarum (E. gallinarum) in the feces, small intestine and liver of (NZW× BXSB)F1 mice. Monocolonzation of germ-free mice with E. gallinarum (EG, here) revealed that it could specifically drive Th17 response, unlike E. faecalis or B. thetaiotaomicron.



Moreover, E. gallinarum could specifically drive  ERV gp70 expression in the liver cells,



and augment anti-nucleic acid antibody response.




Finally, the authors showed that liver tissues from human SLE patients harbored E. gallinarum.


In summary, this study proposes the following patho-mechanism of SLE: when residing in predisposed individuals E. gallinarum causes degradation of gut barrier function, then translocates internally, activates Th17 pathway and initiates "innate" autoimmune phenotype by activating expression of retroviral genes and amplifying endogenous nucleic acid detection system that breaks tolerance checkpoints and leads to auto-antibody formation, Ab-Ag complex deposition in tissues and inflammatory disease exaggeration. The authors proposed antibiotic treatment could provide relieves in certain SLE patients.

However, there are few unanswered questions in this study: first of all, it is clear that E. gallinarum does not induce autoimmunity by itself. Second, If Th17 activity is relevant for E. gallinarum action, then it would have been more valuable for the authors to compare E. gallinarum to segmented filamentous bacteria (SFB) a known inducer of Th17 response in the gut tissue.

posted by David Usharauli



Saturday, March 3, 2018

Specific microbiota species induce serum IgA that protects against sepsis

Some 10 years ago the scientists made observation that microbiota difference between different mouse colonies is responsible for selective TH17 expansion in the gut. Since then, field of immunology was flooded with numerous observations linking gut [and other tissue] microbiota to functional status of immune system.

One such study was recently published in journal Cell Host and Microbe. The researchers observed that serum IgA secreted by bone marrow residing plasma cells (BM PCs) were selectively enriched in mouse colony harboring members of Proteobacteria phylum. More importantly, these serum IgA protected mice during sepsis following gut damage.

Initially, the authors observed that their institute's B6 mouse colony (PENN-SPF) differed from commercial vendor B6 mice in their serum [but not small intestine] IgA status. Co-housing experiment indicated potential involvement of microbiota.



Indeed, 16S ribosomal gene sequencing showed enrichment of Proteobacteria phylum in local mouse colony (and also Deferribacteres).




Serum IgA bound microbiota and sequencing of serum IgA+/IgA- microbiota species confirmed selective enrichment of species within Proteobacteria phylum.




Development of microbiota-specific serum IgA were T cell-dependent.



Finally, serum IgA protected mice against sepsis following gut tissue damage and microbiota invasion (translocation).



In summary, serum IgA, but not intestinal IgA, is produced by bone marrow plasma cells in response to selective microbiota species, mostly from Proteobacteria phylum in mice. These serum IgA could bind microbiota, it developed in a T cell-dependent manner and protected host during gut flora invasion (translocation) in condition such as sepsis. However, it is not clear why serum IgG [in IgA KO mice] could not protect against sepsis in this study since one previous study already showed that serum IgG protected against gram negative bacteria such as E. coli. It is possible that serum IgA and IgG play non-redundant functions by protected against different microbial species.

posted by David Usharauli



Saturday, February 10, 2018

Antigen-specific Foxp3+ Tregs control tolerance to gut pathobiont H. hepaticus

Helicobacter hepaticusH. hepaticus, is an opportunist commensal, a pathobiont, that causes gut inflammation in IL-10 deficient but not in WT mice. A New study in journal Nature from Dan Littman's lab tried to understand basis for such dual nature of host response to H. hepaticus.

The authors have generated transgenic T cells specific for H. hepaticus-unique protein, HH_1713. Next, the authors co-transferred H. hepaticus-specific T cells (HH7-2tg cells) alongside with segmented filamentous bacteriaSFB-specific T cells (7B8tg cells) into WT mice exposed to H. hepaticus. Interestingly, HH7-2tg cells mostly differentiated into RORγt+ Foxp3+ Tregs while 7B8tg cells mostly differentiated into Th17 cells, as observed in earlier studies.



However, similar transfer of H. hepaticus-specific T cells into IL-10KO mice exposed to H. hepaticus mostly yielded inflammatory T cells (Th17 and Th1 cells).



It appears that transcription factor c-MAF control differentiation of H. hepaticus-specific T cells into RORγt+ Foxp3+ Tregs and its deficiency recapitulates H. hepaticus-specific T cells differentiation into inflammatory T helper cells observed in IL-10KO hosts when exposed to H. hepaticus.



In summary, this study indicates that in WT mice harbor H. hepaticus specific Foxp3+ T cells that keep tolerance to H. hepaticus. These induced Foxp3+ T cells are probably generated (or expand) by chain reaction orchestrated by existed antigen-specific natural Tregs since induced Tregs don't develop efficiently when transferred into RAG KO hosts lacking natural Tregs. IL-10 or c-MAF deficiency could alter overall microbiota composition (unrelated to H. hepaticus) and drive shift from Treg program into inflammatory pathway.

posted by David Usharauli



CD4 T cells silence innate over-activation to gut microbiota

A simple but very effective study was published in journal Nature from Ron Germain's lab. His group is known for publishing high quality in situ microscopy data combined with cellular analysis. New study continues this trend. 

In this study the authors analyzed pattern of phosphorylation of STAT3 transcription factor in small intestine derived from various immune deficient mouse strains. Compared to WT mice, pSTAT3 staining in RAG1 KO gut tissue (lacking adaptive immune system) was significantly up-regulated. 



Analysis of antibiotic-treated or germ-free mice indicated that pattern of pSTAT3 staining in RAG1-KO was correlated with the presence of gut microbiota.




Interestingly, longitudinal analysis showed that pSTAT3 staining inversely correlated with  maturation of adaptive immune system post weaning (between 4-20 weeks). 



Co-housing experiments showed that T cells, but not B cells, played a role in silencing innate pSTAT3 over-activation.



And out of T cells, it were CD4 T cells and class II antigen-presentation that played the role in pSTAT3 silencing.



Finally, both Tregs and SBF-specific Th17 cells (7B8 transgenic T cells) could mediate silencing of pSTAT3 over-activation. Both T cell type could down-regulate STAT3 phosphorylation in innate and epithelial cells but the mechanisms could be different. 




In summary, this study showed that persistent pSTAT3 over-activation observed in mice deficient for CD4 T cell function could explain some of chronic metabolic shifts observed in clinical settings. 

posted by David Usharauli


Tuesday, February 6, 2018

T1D target epitope from zinc transporter 8 (ZnT8) cross-reacts with commensal bacteria

Type 1 diabetes (T1D) is considered autoimmune disease. Of course, in humans, we don't have a direct evidence that islet-specific auto-reactive T cells and auto-antibodies found in peripheral blood from T1D patients are indeed responsible for tissue damage. Such evidence would require T/B cell and Ab depletion experiment that is not feasible. Autoimmune nature of T1D is basically extrapolated from mouse studies or in vitro antigen binding assays.   

Several islet antigens are known to represent targets in T1D, such as preproinsulin (PPI), glutamic acid decarboxylase (GAD), insulinoma-associated protein-2 (IA-2), islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) and more recently described zinc transporter 8 (its peptide ZnT8186–194).

New study in Science Immunology found that ZnT8186–194-specific CD8 T cells are largely similarly present in both T1D patients and healthy controls and that ZnT8186–194-specific CD8 T cells could recognize (cross-react) peptide derived from gut commensal microbe Bacteroides stercoris.

Staining with ZnT8186–194-specific HLA class I multimers (MMr) and other functional antigen-specific assays found that T1D and healthy controls harbored largely similar number and functional ZnT8186–194-specific CD8 T cells.




Interestingly, ZnT8186–194-specific CD8 T cells could be double stained with HLA class I multimer + peptide derived from B. stercoris, a commensal bacterial species found in gut flora. It is not the first time such cross-reactivity has been observed between islet-specific CD8 T cells and commensal bacteria. Previously, at least two bacterial species have been identified to cross-react with IGRP-specific CD8 T cells.





In summary, this study indicates that deletion of auto-reactive CD8 T cells in the thymus is not sufficient to prevent autoimmunity and that regulatory mechanisms operating in the periphery is necessary to prevent initiation of auto-reactive attack by circulating ZnT8186–194-specific CD8 T cells (probably Tregs the authors had in mind). Cross-reactive peptide derived from B. stercoris could play role in priming of ZnT8186–194-specific CD8 T cells in absence of regulatory circuit. But how and why such antigen-specific tolerance breakdown happens in one and not in another is not clear at this stage.

posted by David Usharauli


Thursday, January 25, 2018

Recognition of microbiota-derived N-formyl methionine peptides by non-classical MHC class I, H2-M3-restricted CD8 T cells

A new study in journal Cell revealed that a specialized subset of CD8 T cells recognize conserved microbial derived N-formyl methionine peptides in context of non-classical MHC class I molecule H2-M3.

Using skin commensal Staphylococcus epidermidis (S. epidermidis) challenge model, the authors showed that recognition of this microbe by CD8+ T cells specifically relied on H2-M3 rather than other MHC molecules.



H2-M3 has been known to bind peptides that contain an N-formyl methionine (fMet), which is required to initiate protein translation in bacteria and mitochondria. Indeed, fMet peptide:H2-M3 tetramer (f-MIIINA:H2-M3) could stain a population of CD8 T cells from skin or lymph nodes. Interestingly, half of tetramer positive CD8 T cells were CD44hi even in germ-free mice indicating cross-reactivity with other antigens or "ready-made" origin similar to thymus-derived Tregs.



To show biological significance of these CD8 T cell population recognizing commensals, the authors used H2-M3 KO mice and wound healing experiment. The authors claim that in the absence of H2-M3 wound healing was delayed, though data do not strongly support such assertion.



In summary, the authors described yet another T cell population recognizing products from bacteria. Because such recognition does not produce inflammation the authors suggest it could be involved in wound repair. But wound repair model provided very minimal support for such hypothesis. Basically, they missed the central point to make this paper relevant. So how it ended up in Cell? Ask editors. I could come up with couple of suggestions. When the paper's authors list includes Giorgio Trinchieri, John O’Shea and senior author, Yasmine Belkaid, all heads of big labs at NIH, it is quite difficult to say no.

posted by David Usharauli


Thursday, January 18, 2018

Receptor-ligand specific labeling of immune cell interactions

This week journal Nature published new study in immunology that could be best described as a method paper. I personally don't understand the value of this paper been in Nature. Only positive characteristic I see in it is that experiments reported are done in a classical, cellular immunology "fashion" and very easy to follow and understand. Lets examine.

The new method, called LIPSTIC, which this study reported is about labeling receptor-ligand pair with naturally occurring enzyme, the Staphylococcus aureus transpeptidase sortase A (SrtA). SrtA appears to covalently transfers a substrate containing motif ‘LPXTG’ to a nearby oligoglycine (G5). Basically, receptor is genetically fused with SrtA and ligand is fused with G5 and when they interact, SrtA catalyses the transfer of the substrate onto the G5-tagged receptor. This transfer can be visualized by attaching to the substrate small labels such as biotin or a fluorophore.  



First the authors showed in vitro and ex vivo that the substrate transfer was specific to fused receptor-ligand pair and did not occur when enzyme was inactive or fused to unrelated receptor. Most of the reported experiments were done using CD40L/CD40 pair (CD40 signaling is relevant for DCs and CD8 T cell activation by CD40L expressing CD4 T cells).



Receptor-ligand specificity was maintained in vivo as well. Because CD40L upregulation on CD4 T cells depends on antigen-specific interactions, substrate transfer were restricted to those CD40+ DCs that were pulsed with cognate peptide (OVA).



However, this antigen-specific CD40L/CD40 interaction was maintained only for initial 10h-24h period. When OVA-specific T cells were left with DCs for longer period (48h) then even DCs pulsed with irrelevant peptide (LCMV peptide) got labeled with substrate. 



It is not clear what are the biological consequences of such non-specific T/DCs interactions. Are these two different DCs activated antigen or non-antigen specific manner somehow different with the regard of activation of CD8 T cells? We don't know. The problem with such model is that if activated CD4 T cells expressing CD40L can interact with CD40+ DCs and activate it (license it, to use polly matzinger's words) then we should expect that body should harbor only activated DCs because body constantly contains some number of CD40L+ activated CD4 T cells specific for all kind of antigens. It is possible high number of T cells transferred in these experiments created an artificial outcome.

In summary, this study showed new method how to label receptor-ligand pair in vivo. However, overall relevance of this method is not clear at present.

posted by David Usharauli



Saturday, January 6, 2018

Microbiota-wide association studies and PD-1 immunotherapy

This week Science published 3 back-to-back studies with the findings that responses to PD-1 immunotherapy in cancer patients could be stratified based on presence of certain microbiota species (at least two of these studies were published couple of weeks back as first release papers). 

The trouble is that all three papers found different set of microbiota who they thought mediated responsiveness to PD-1 immunotherapy (dominated by Bifdobacterium, Akkermansiaor Faecalibacterium). 



In one study, it was actually a difference between set of beneficial microbiota versus nonbeneficial ones (not simply a single species), above certain ratio (>1.5), that determined responsiveness to PD-1 therapy.



Moreover, study of germ-free mice transplanted with opposite sets of microbiota (derived from 3 responders/nonresponders) were inconclusive because 1 set of microbiota from each group showed reverse effect with PD-1 immunotherapy. 



In summary, we have no clear understanding of these results. There is no way to predict if the same microbiota set would provide any benefit to a given patient. In general, presently microbiota research lacks direction and rules necessary to untangle its complexity

As far as I know, the model we have developed, SPIRAL, is the only one that provides a rational how to identify specific microbiota species. Right now it is just a guideline but when fully developed it will look similar to period table-like map that will make it easy to accurately pinpoint microbiota species relevant for antigen-specific immune response in any given individual.

posted by David Usharauli