Multiple sclerosis, TH17 and vitamin A

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease. Recent studies shed light on its autoimmune component and offer evidence for the use of vitamin A in consideration of the premiere importance of Treg and Th17 or Th40 balance.An excellent paper, highly recommended for any practitioner managing autoimmune disorders in general, that was just published in Autoimmunity Reviews examines the balance between pro-inflammatory Th17 cells and regulatory T cells in autoimmune and inflammatory diseases. Commenting on Th17Treg balance in general:

"Th17 and Treg cells have opposite roles in the development of autoimmune and inflammatory diseases. While Th17 cells promote autoimmunity, Treg cells serve to control it and therefore play a very important role in autoimmune pathogenesis by maintaining self- tolerance and by controlling expansion and activation of autoreactive CD4+ T effector cells. The control of Th17/Treg balance appears also critical in the development of these diseases...Developmental pathways of Th17 and Treg cells are reciprocally regulated and can influence the outcome of immune responses, partic- ularly in autoimmune and inflammatory diseases."

Specifically in regard to multiple sclerosis:

"MS is a chronic inflammatory disease that leads to brain inflammation and that may involve a break in tolerance. Th17 cells are considered to be important in multiple sclerosis pathogenesis. IL-17A gene is overexpressed in biopsy samples taken from the brains of patients with MS and Th17 cells are present in high proportion in active MS lesions. Treg cells are also implicated in MS. It was reported that a disturbance in the development and function of Treg subpopulations and also an altered frequency of Treg cells are associated with disability status in relapsing remitting MS patients. Furthermore, CD39-expressed Treg cells have the potential to suppress IL-17 production and the pathogenic Th17 cells. So in MS pathogenesis, maintaining Th17/Treg balance appears to be critical."

No wonder vitamin D has come to the fore lately in the treatment of multiple sclerosis since it is critical for Treg development. The authors conclude with an important statement that embraces all autoimmune conditions in addition to multiple sclerosis:

"Th17 and Treg cells are both implicated in inflammatory and autoimmune diseases. Th17 cells are involved in the induction and propagation of pathologies whereas Treg cells inhibit autoimmunity and are responsible for tolerance against self-antigens. Th17 and Treg cells share common factors, such as TGF-β, that affect their development and generation. The balance between inflammation (Th17 cells) and tolerance (Treg cells) may influence pathology or disease outcomes in autoimmune diseases, including RA and MS. It is though that if this critical balance is deviated in favor of Th17 cells and against Treg cells, the severity of disease could be significantly enhanced. Such contribution justifies developing new therapeutic means to keep an adequate balance between pathogenic Th17 cells and protective Treg cells, for preventing the development and extension of autoimmune and inflammatory diseases." 

In light of the above, a paper recently published in the journal Acta Medica Iranica discussing the use of vitamin A to restore Th17/Treg balance in multiple sclerosis is of special interest. The authors note:

"MS is an autoimmune and neurodegenerative disease of the central nervous system. Inflammation in MS leads to both demyelination and axonal loss...The correlation between damage to the central nervous system and inflammatory reactions during progression of the disease can be understood in terms of existing myelin specific autoreactive T cells in the peripheral blood and cerebrospinal fluid (CSF) of MS patients. This “activated state” of myelin-reactive T cells observed in MS patients is associated with up-regulation of adhesion molecules that make these cells more prone to interact with the blood–brain barrier (BBB) and drive an inflammatory response directed against myelin antigens within the CNS. Therefore, any change in immune response induced by CD4+ cells, particularly the imbalance between Th1/Th2 and also Th17/Treg and subsequent changes in their cytokine's secretion such as IFN-γ, IL-2( Th1), IL-4 (Th2), IL-17(Th17) IL-10 and TGF-β (Treg) can lead to damage and atrophy of the brain...Cytokine changes in MS are characterized by increased levels of IFN-γ, IL-2, and IL- 17 and decreased levels of IL-4, IL-10 and TGF-β."

So of paramount practical importance...

"CD4+ Treg cells can suppress inflammatory responses and induction or enhancement of creation of their cytokines such as TGF-β represents a potentially interesting option for the treatment of MS. Therefore, therapeutic strategies that lead to shift the immune response reactions from Th1 to Th2 and Th17 to Treg cells may be effective in the treatment of MS. Retinoic acid inhibits Th1 and Th17 polarization and induces the differentiation of Th2 and Treg cells. Other research has demonstrated that all Trans’ retinoic acid (ATRA) causes a shift in gene expression of Th1, and Th17 cytokines and their transcription factors to Th2 and T regulatory cells. This study examines the effect of vitamin A supplementation as synergistic effect on MRI changes, cytokine levels and gene expression in patients with MS."

(Retinoic acid and ATRA are metabolites of vitamin A.) The authors also state:

"Vitamin A and its metabolites such as retinoic acid (RA) regulate immune homeostasis by induction of regulatory T cells. Studies have shown that RA also elicits pro-inflammatory Th1 and Th17 cells’ responses to infection*. Retinoic acid receptor alpha (RARα) is a critical mediator for these effects. These findings demonstrate a functional role for the RA-RARα axis in the development of both regulatory and inflammatory reactions of adaptive immune system...Vitamin A deficiency is associated with decreased Th2 responses. Vitamin A supplement inhibits Th1 and promotes Th2 differentiation in vitro and In vivo...Therefore, retinol and its metabolites present promising possibilities to prevent inflammatory reactions, central nervous system degeneration and disease progression."

Clinical note*: since vitamin A helps fight infection while inducing regulatory T cells to maintain immune balance it is well worthy of consideration in acute, especially mucosal, infections.With these dynamics in mind plus the challenges of nailing a diagnosis of multiple sclerosis, practitioners should be aware of Th40 cells, a new biomarker for MS revealed by a study just now published in the Journal of Neuroimmunology. The authors state:

"Multiple Sclerosis (MS) is a chronic inflammatory, neurodegenerative disease. Diagnosis is very difficult requiring defined symptoms and multiple CNS imaging. A complicating issue is that almost all symptoms are not disease specific for MS. Autoimmunity is evident, yet the only immune-related diagnostic tool is cerebral–spinal fluid examination for oligoclonal bands. This study addresses the impact of Th40 cells, a pathogenic effector subset of helper T cells, in MS."

They examined MS patients for Th40 cell levels in peripheral blood resulting in findings comparable to autoimmune type 1 diabetes:

"The levels were significantly elevated compared to controls including healthy non-autoimmune subjects and another non-autoimmune chronic disease. Classically identified Tregs were at levels equivalent to non-autoimmune controls but the Th40/Treg ratio still predicted autoimmunity."

Moreover...

"The cohort displayed a wide range of HLA haplotypes including the GWAS identified predictive HLA-DRB1*1501 (DR2). However half the subjects did not carry DR2 and regardless of HLA haplotype, Th40 cells were expanded during disease. In RRMS [relapsing-remitting MS] Th40 cells demonstrated a limited TCR clonality. Mechanistically, Th40 cells demonstrated a wide array of response to CNS associated self-antigens that was dependent upon HLA haplotype. Th40 cells were predominantly memory phenotype producing IL-17 and IFNγ with a significant portion producing both inflammatory cytokines simultaneously suggesting an intermediary between Th1 and Th17 phenotypes."

The authors highlight their key conclusions:

• We describe CD40 as a T cell biomarker, defining Th40 cells, in MS.
• Th40 cells are significantly elevated regardless of HLA haplotype in MS.
• Th40 to Treg ratio is more predictive of autoimmunity than either subset alone.
• Th40 cells from each patient demonstrate unique CNS antigen signatures.

In other words, Th40 cells appear elevated regardless of the genotype of the patient. Unique neuro-antigen autoimmune targets are consistent with the case variability of symptom presentation. Most importantly, the balance between Th40 and Treg cells is decisive, returning us to premiere consideration of interventions that can elevated Treg function.