β-synuclein specific CD4+ T cells invade brain grey matter to cause array of MS-like symptoms

β-synuclein specific CD4+ T cells invade #brain grey matter and cause array of MS-like #symptoms in a rat model of human #MultipleSclerosis. Interestingly, the most useful distilled data points were in suppl materials. #immunology #autoimmunedisease https://t.co/NbIt5ijxuR

— David Usharauli (@3DiMMUNE) March 5, 2019

highlights from paper
2. Such exclusive invasion of brain grey matter were primarily correlated by pattern of #antigen (β-synuclein) expression. #autoimmunedisease #immunology pic.twitter.com/1r9ROgtTDV

— David Usharauli (@3DiMMUNE) March 5, 2019

Some thoughts: here the authors have used either WT or transgenic rat expressing β-synuclein-specific T cells. Diseases were induced either following direct immunization of transgenic rats or adoptive transfer of activated β-#synuclein-specific T cell blasts. #immunology

— David Usharauli (@3DiMMUNE) March 5, 2019

Con't: immunologists have fairly good idea about processes that represent immune response but at presently it is still unknown how immune response is #initiated naturally or how it is #stopped. This is Achilles heels of current experimental models in #immunology.

— David Usharauli (@3DiMMUNE) March 5, 2019

New synthetic molecule prevents autoimmunity without compromising anti-pathogen immunity

In December of 2016 Science Translational Medicine published new study where the authors introduced new, low-molecular weight compound that specifically inhibited autoimmune/allergic responses while sparing anti-pathogen immune response.

This new molecule, AX-024, specifically targets adaptor protein Nck that is involved in low affinity TCR signaling. 

It does not affect signaling delivered via IL-2, BCR or PMA/Ion stimulation.

AX-024 inhibited TLR7/8 agonist, imiquimod (IMQ), induced psoriasis skin symptoms in mice.

Also, AX-024 significantly reduced clinical symptoms associated with mouse model of human multiple sclerosis (MS). Such effect of AX-024 was superior to Fingolimod, a sphingosine 1-phosphate receptor modulator approved for the treatment of relapsing-remitting MS.

Notably, AX-024 in therapeutic dosage did not impair anti-pathogen immunity or memory generation.

In summary, by blocking Nck adaptor protein involved in low-affinity TCR signaling, AX-024 inhibited autoreactivity while preserving necessary capacity for anti-pathogen immunity. Such property makes it desirable candidate for clinical trials in humans.

David Usharauli 

Spontaneous death of myelin-producing oligodendrocytes could trigger delayed MS-like symptoms

I usually don't check Nature Neuroscience. It does not typically publish immunology-related studies [though MS studies are of interest]. So I was surprised to see such "heavily" packed immunology article there and decided to review it to understand how it ended up there.

It is immediately clear that is not written from immunologist point of view. In general, inter-disciplinary studies are encouraged but if it is not done properly it produces lesser quality research. 

Now, in this paper the authors found that conditional deletion [by death] of brain glial cells, oligodentrocytes, who are responsible for myelin production, triggers late onset MS-like neurological symptoms.

To this end, the authors have used Plp1-Cre-ER^T;ROSA26-eGFP-DTA mouse model where tamoxifen injection releases stop signal from diphtheria toxin A production in oligodendrocytes leading to their death. It appears that this is a rare model of oligodendrocyte deletion where mice actually survive long-term (but it appears this DTA model show late-onset [starting at weeks 26] "leakiness" in absence of tamoxifen injection. This knowledge in itself creates host of issues in data interpretation).  

So, the authors noticed that starting 40 weeks post tamoxifen injection [but not at 10 weeks], spleen and cervical lymph nodes of Plp1-Cre-ER^T;ROSA26-eGFP-DTA mice contained MOG-specific effector T cells. These were accompanied with clinical symptoms of EAE.

Similar results were found with 2D2 transgenic CD4 T cells [specific for MOG] transferred into tamoxifen-treated Plp1-Cre-ER^T;ROSA26-eGFP-DTA host.  

Now, next experiments were quite surprising. To clearly show the role of T cells in the development of late onset MS-like symptoms in tamoxifen-treated Plp1-Cre-ER^T;ROSA26-eGFP-DTA mice the authors tried to cross this DTA model with RAG KO mice. Interestingly, these T/B cell-deficient DTA mice did not survive after tamoxifen injection, implying that recovery from acute oligodendrocyte deletion [following tamoxifen injection] somehow required presence of T or B cells [reminds of studies done by Michal Schwartz lab]. However, the authors neither tried to use CD3KO or B cell KO or simply Ab depletion to test these hypotheses.

Other set of experiments with adoptive transfer of T cells harvested from tamoxifen-treated Plp1-Cre-ER^T;ROSA26-eGFP-DTA mice into RAG deficient mice (but not in WT host) produced MS-like symptoms.

In the remaining experiments the authors tried to show that injection of MOG peptide coupled to nanoparticles could tolerize self-reactive T cells.

So what we learned from this study? First, I am surprised that it even get into Nature Neuroscience [it does not belong there]. Now, this could mean few things: (1) this research was rejected from Nature Immunology and ended up in Nature Neuroscience; (2) It was directly sent to Nature Neuroscience but reviewed by non-immunologists; (3) standards for Nature Neuroscience is much lower compared to Nature Immunology, in general.

David Usharauli

Depletion of "hybrid" B cells could explain benefits of anti-CD20 immunotherapy in MS patients

Multiple Sclerosis (MS) is believed to be an autoimmune disease. During MS, the patient's own immune cells attack peripheral nerves' myelin sheath disrupting proper signal transmission. In mouse model of MS, called experimental autoimmune encephalomyelitis (EAE), several myelin proteins have been identified as such targets (such as MBP and MOG). 

While self-specific T cells are widely thought to play a pathogenic role in MS progression, clinical trials revealed surprising benefits of B cell depletion in MS. Mechanism is unknown.    

Now new paper is Science Translational Medicine provided initial data suggesting that depletion of pro-inflammatory GM-CSF secreting B cell subset could explain the clinical benefits of anti-CD20 antibody therapy in MS.

First, the authors showed that activated peripheral B cells from healthy donors express pro-inflammatory cytokine GM-CSF. Interestingly, this B cell population does not overlap with B cell population expressing anti-inflammatory cytokine IL-10.

Next, the authors showed that activated B cells from MS patients tend to express more GM-CSF compared to B cells from healthy donors.

In vitro co-culture of B cells and macrophages revealed that B cell-derived GM-CSF contributed to Th1-type macrophage polarization.

More complex co-culture experiments showed that macrophages derived from MS patients soon after B cell depletion produced less of pro-inflammatory cytokine IL-12p40.

And more importantly, this tendency was maintained even after 1 year of B cell depletion, even though new B cell came back by this time.

This points to a re-configuration of cytokine network in anti-CD20 antibody treated MS patients such as reversal of B cell-derived GM-CSF/IL-10 ratio.

In summary, this study provides additional clues why anti-CD20 antibody depletion might benefit MS patients. Antibody-independent function of B cells is a novel concept [and not widely known or accepted]. One of the reasons for this resistance is lack or inadequate knowledge of B cell receptor specificity of such specialized B cell subset. We need to go one step further and connect the dots between BCR specificity or other innate receptors and B cell's "hybrid" function. Only by developing this biological "framework" can we fully understand the role B cells play in health or diseases.

If you are interesting in science of MS, I will recommend a book by Susan Quinn's "Human Trials: Scientists, Investors, And Patients In The Quest For A Cure" (2001).

David Usharauli