Gut-associated IgA repertoire diversity is maintained independently of continuous gut flora exposure

Gut-associated immune system has a delicate task to maintain tolerance towards endogenous gut flora and food-associated antigens while at the same time to detect and mount protective immune response against invading pathogens.

Clonal size and repertoire diversity of gut-associated IgA pool are influenced by presence of flora antigens. However, little is known of the mechanisms that control gut IgA repertoire stability in response to antibiotic treatment or pathogen exposure.

This new paper in Nature Immunology tried to do exactly this. The authors serially sampled and sequenced individual mouse gut IgA pool longitudinally, after (a) antibiotic, (b) pathogen or (c) defined flora colonization, to determine changes in IgA repertoire diversity.

Initially, the authors showed that IgA repertoire diversity in germ-free mice exposed to various combination of flora (mono or poly-colonization) correlated with richness of colonized flora.

However, when GF mouse gut IgA pool was analyzed, before and after flora exposure, the authors noticed no major IgA repertoire change, implying flora-independent IgA repertoire maintenance (through it is not quite clear here how the authors differentiate IgA repertoire "diversity" versus repertoire "similarity").

Interestingly, the authors made similar observation in gut IgA pool from healthy volunteers exposed to antibiotics.

In addition, the article contains several other experiments, but I was not able to decipher their meaning or relevance to the concept, so I did not discuss them here. In general, paper is poorly written and lacks natural flow between experimental hypothesis and experimental results.

In summary, my interpretation of this paper is following: (a) gut IgA repertoire diversity is non-overlapping between individuals, including genetically identical mice, (b) gut IgA repertoire stability is minimally influenced by exposure to antibiotics or new flora (however if it is true and gut immune system maintains its integrity upon antibiotic exposure, then how can we account for frequent GI issues following antibiotic treatments?)

David Usharauli

Determinants of T cell exhaustion during chronic viral infection and autoimmunity

Typically when we think about ordinary immune response, we imagine several finite steps involving T and B cells, such as antigen recognition and initiation of antigen-specific clonal expansion, control of antigenic spread and elimination of infected cells and finally return to quiescent state and memory establishment.    

This scenario represents what ordinary is called immune response to transient (acute) antigenic stimulation. However, how does host immune system respond to persistent (chronic) antigenic stimulation, for example, chronic viral presence (HIV, HVB, HCV, Malaria, TB) or autoimmune disease (self-antigens)? Are the mechanisms that control immune response similarly activated during acute or chronic antigenic presence?

As you can see many infectious diseases with no effective vaccines fall exactly in the category of chronic infections (HIV, HBV, HCV, Malaria, TB). This is not a random outcome. There should be some biological or immunological underpinning to account for our failure to develop such vaccines. 

This new paper in journal Nature provided some additional results that may help us to better understand mechanisms controlling chronic immune responses. To tell the truth, it is quite difficult-to-digest article with lot of large data set analyses. The paper was under review for more than 1 year and its main finding regarding molecule KAT2B isn't even mention in their abstract. Strange. So we just need to assume that their analyses are done correctly and are statistically valid.

In this paper the authors tried to correlate CD8 T cell exhaustion phenotype with the clinical outcome (flare-free survival) of patients suffering from various autoimmune diseases. Murine chronic LCMV infection-associated CD8 T cell exhaustion phenotype was used as a reference. 

First, the authors noticed that unlike coordinated up-regulation of several inhibitory receptors during murine chronic LCMV infection, CD8 T cell phenotype from patients with autoimmune diseases displayed distinct disease-selective up-regulation of exhaustion-associated inhibitory receptors.

Interestingly, for each patient with autoimmune diseases, CD8 T cell exhaustion phenotype correlated with a favorable prognosis.

Next, in vitro experiments showed that fine balance between incoming co-stimulatory (e.g. CD2) and co-inhibitory (e.g. PD-L1) signals may determine exhaustion phenotype of CD8 T cells during persistent antigenic stimulation (one caveat: anti-CD3, anti-CD28 or anti-CD2 antibody stimulation are not physiological mode of activation, at all).

Finally, the authors showed that level of expression of KAT2B (top-ranked CD4 T cell co-stimulation candidate) could predict (1) favorable response during chronic viral infection and/or positive host response to vaccination, and (2) poor prognosis during autoimmune diseases.

In summary, these results indicate that treatment of chronic viral infection and chronic autoimmune diseases may require activation of opposite receptors.

David Usharauli

Mechanism of high fat diet (HFD)-induced skin inflammation

High fat diet (HFD) has been implicated in a metabolic syndrome that combines several set of diseases such as Type II diabetes, obesity, etc. Frequently, metabolic syndrome is associated with skin inflammation (acne, dermatitis, etc). Mechanism is unknown.

A new paper in journal Immunity provided results that indicate that epidermal fatty acid binding protein, E-FABP, is a direct link between skin inflammation and HFD.

This is a simple, observation-type of research. I would say that the authors were lucky to get it published in Immunity. Though, I liked the idea that the authors developed the concept for the paper through serendipitous observation.

Initially, the authors showed in their mouse facility, B6 mouse strain fed HFD for 3-6 months developed skin lesions that correlated with fat content in the diet.

Next, the authors found that lesion skin from HFD-fed mice contained higher proportion of macrophages.

These macrophages from lesion skin tend to produce high levels of IL-1β and IL-18.

Analysis of E-FABP expression (fatty acid chaperons) showed its up-regulation in lesion skin and macrophages from HFD-fed mice.

Finally, using E-FABP knockout mice, the authors showed that absence of E-FABP prevented development of skin lesions in HFD-fed mice (with no effect on weight gain).

In summary, these results indicate that excess of dietary fat (saturated fat) induces skin inflammation via epidermal fatty acid binding protein. The authors think it has to do with activation of NALP3 pathway in macrophages by excess saturated fat (leading to IL-1β and IL-18 production) and recruitment of T cells secreting IFN-γ and IL-17 (though those are correlative results and not particularly persuasive). However, effect of E-FABP on skin lesion development is striking.

David Usharauli