Clonal IgA and IgG autoantibodies from individuals .... identify an arthritogenic strain of Subdoligranulum, 2022, Chriswell

[Mij]

A bacterial driver of arthritis
Autoantibodies can be detected in individuals at risk for developing rheumatoid arthritis (RA) before development of clinical disease. The source of these autoantibodies, however, remains unclear. Here, Chriswell et al. identified that IgG and IgA autoantibodies from individuals who are at risk for RA cross-react against gut bacteria in the Lachnospiraceae and Ruminococcaceae families. Further analysis identified a bacterial strain from the Subdoligranulum genus that was associated with autoantibody development. Mice colonized with this Subdoligranulum isolate developed arthritis with pathology similar to human RA.

These findings suggest that this Subdoligranulum strain may be a major contributor to RA autoantibody development.


https://theconversation.com/newly-d...-a-culprit-behind-rheumatoid-arthritis-193267

@Jonathan Edwards

 

[Jonathan Edwards]

Sounds like the same old story being rolled out.
There was never any reason to think that a foreign antigen was needed to explain the 'source' of autoantibodies.
Poor old Robin Coombs would be sad that this idea from the 1960s is still being flogged despite its hooves pointing skywards.

 

[Hutan]

Clonal IgA and IgG autoantibodies from individuals at risk for rheumatoid arthritis identify an arthritogenic strain of Subdoligranulum
Chriswell et al
Abstract
The mucosal origins hypothesis of rheumatoid arthritis (RA) proposes a central role for mucosal immune responses in the initiation or perpetuation of the systemic autoimmunity that occurs with disease. However, the connection between the mucosa and systemic autoimmunity in RA remains unclear.

Using dual immunoglobulin A (IgA) and IgG family plasmablast–derived monoclonal autoantibodies obtained from peripheral blood of individuals at risk for RA, we identified cross-reactivity between RA-relevant autoantigens and bacterial taxa in the closely related families Lachnospiraceae and Ruminococcaceae. After generating bacterial isolates within the Lachnospiraceae/Ruminococcaceae genus Subdoligranulum from the feces of an individual, we confirmed monoclonal antibody binding and CD4+ T cell activation in individuals with RA compared to control individuals. In addition, when Subdoligranulum isolate 7 but not isolate 1 colonized germ-free mice, it stimulated TH17 cell expansion, serum RA–relevant IgG autoantibodies, and joint swelling reminiscent of early RA, with histopathology characterized by antibody deposition and complement activation. Systemic immune responses were likely due to mucosal invasion along with the generation of colon-isolated lymphoid follicles driving increased fecal and serum IgA by isolate 7, because B and CD4+ T cell depletion not only halted intestinal immune responses but also eliminated detectable clinical disease.

In aggregate, these findings demonstrate a mechanism of RA pathogenesis through which a specific intestinal strain of bacteria can drive systemic autoantibody generation and joint-centered antibody deposition and immune activation.

paywall

 

[Jonathan Edwards]

In addition, when Subdoligranulum isolate 7 but not isolate 1 colonized germ-free mice, it stimulated TH17 cell expansion, serum RA–relevant IgG autoantibodies, and joint swelling reminiscent of early RA, with histopathology characterized by antibody deposition and complement activation.

That's a give away. The histopathology of RA is not characterised by antibody deposition or complement activation. It is characterised by macrophage activation and cytokine effects. Antibody deposition is a feature of completely different pathologies like lupus nephritis. Complement activation just produces oedema and polymorph infiltration.

I am afraid this is just made up.

 

[Hutan]

Complement in the Initiation and Evolution of Rheumatoid Arthritis 2018 ?

An important piece of evidence linking complement activation to pathogenesis in RA was that C1 staining was negative in normal articular cartilage and positive in degenerating cartilage biopsies from all RA patients examined (143). This study strongly implicated the involvement of the CP in the pathogenesis of RA. C3b was also present on the cartilage surface of RA patients; thus, this study clearly showed that C1s can activate the downstream complement cascade thereby causing irreversible damage. It has also been shown that the level of C1q in serum correlates with clinical disease activity (CDA) in RA patients (144–146).

I've seen enough bad papers to know that what the title says is not necessarily right. And there's a lot of focus on incomplete mouse models of RA in that 2018 paper. Maybe the complement activation is just a downstream effect, although this paper suggests a role for RA initiation.

I would not be surprised if the complement system is part of the story with the type of ME/CFS that I and my family have, so it's interesting to try to understand how it works.

 

[Jonathan Edwards]

I've seen enough bad papers to know that what the title says is not necessarily right. And there's a lot of focus on incomplete mouse models of RA in that 2018 paper. Maybe the complement activation is just a downstream effect, although this paper suggests a role for RA initiation.

But this piece of data is just pathetic. It talks of complement staining in degenerate cartilage. Cartilage is normally alive and the living chondrocytes continually produce glycosaminoglycan and hyaluronan which ooze gradually out through the collagen matrix a bit like grease from a stern gland constantly oozing out through the fabric collar around a prop shaft that stops sea water running back up into a yacht along the spinning shaft.

When cartilage is damage in RA it is because the chondrocytes have been killed, probably by lack of glucose in a joint full of inflammatory fluid. (We have known about the low levels of glucose in inflammatory fluid for fifty years or more. The fact that the chondrocytes are dead and their lacunae empty has been known for a century.) Once dead the cartilage becomes like a limp rag, which takes up any protein nearby just as the fabric collar around a prop shaft takes up algae.

So finding complement protein staining dead cartilage means nothing whatever.
The incompetence of inflammation scientists is mind-boggling really. I subscribe to Academia.com and as part of that I get notifications of citations of my papers. Every day there are citations of my key NEJM Rituximab trial. But sadly, every day there are also citations of work I did in the 1980s that was almost as bad as this paper - in some cases as bad. That was when I was a green doctoral student with a rather hairbarined supervisor.