Sjögren’s syndrome: calming the B cell attack

Summary:

  • B cells play an important role in Sjögren’s syndrome.
  • NF-κB is a key factor in B cell autoimmunity.
  • There are benign ‘natural’ pharmaceutical agents that calm NF-κB and B cell activity.
  • Sex steroids must also be evaluated.

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease characterized by progressive destruction of the salivary and lachrymal glands. This causes dryness of the mouth and eyes and, as with most autoimmune diseases, various other tissues are also subject to attack. A paper just published in the Journal of Autoimmunity reviews the recent discoveries that have advanced our understanding of the way the immune system becomes dysregulated in Sjögren’s syndrome and, therefore, how to treat it. The authors state:

“T cells were originally considered to play the initiating role in the autoimmune process, while B cells were restricted to autoantibody production. However, recent years have seen growing evidence that the roles of B cells in pSS pathophysiology are multiple, and that these cells may actually play a central role in the development of the disease.”

They describe how over-stimulated B cells, distributed abnormally in both the salivary glands and peripheral blood, produce excessive amounts of immunoglobulins and autoantibodies. Furthermore…

“B cells control T-cell activation by different means: B effector cells guide Th1 or Th2 differentiation, whereas regulatory B cells inhibit T-cell proliferation. Several B-cell specific cytokines, such as BAFF or Flt-3L, are instrumental in the occurrence of B-cell dysfunction.”

And as we know…

“Chronic and excessive stimulation of B cells may lead to the development of lymphoma in pSS patients.”

Building on the use of autoantibodies and B cell subset analysis for the clinical diagnosis of Sjögren’s syndrome, B cell depletion therapies such as Rituximab, a monoclonal antibody directed at CD20 B cells, have been developed.

A range of epithelial tissues can be attacked in Sjögren’s syndrome hence the descriptive term autoimmune epithelitis. Peripheral neuropathies and primary biliary cirrhosis are particularly notable. Trigeminal neuralgia has also been observed. But what does the insight into B cell dysregulation imply for therapies? The authors of another paper in the Journal of Autoimmunity suggest that therapies aimed at B-cell depletion and regulation of Th17 cells and the inflammatory cytokines IFNα and BAFF for the treatment of Sjögren’s syndrome.

On the practical side, NF-κB (nuclear factor kappa B) plays a prominent role in Sjögren’s syndrome as it does with autoimmunity of most types.This is highlighted in a study recently published in the Japanese Journal of Clinical Immunology. The authors observe:

“The adaptor molecule NF-kB activator 1 (Act1) plays an important role in the homeostasis of B cells by attenuating CD40 and B cell-activating factor belonging to the tumor necrosis factor family receptor (BAFFR) signaling.”

In other words, Act1 messenger RNA’s job is to calm down NF-κB expression. They investigated the role of Act1 in the pathogenesis of Sjögren’s syndrome by examining Act1mRNA expressions in B cells from patients and correlated Act1 with the clinical manifestations of Sjögren’s syndrome. This proved significant:

“We showed the low level of Act1mRNA expression in patients with SS and reciprocal association of Act1 with serum IgG level. Diminished Act1mRNA expression in SS may be associated with B cell hyperactivity and elevated immunoglobulin production in SS by uncontrolled B cell activation signal through CD40 and BAFFR.”

Is there evidence for any agents that are ‘natural’ or benign in controlling NF-κB expression to ameliorate Sjögren’s syndrome and other inflammatory disorders? A study recently published in PLoS One (Public Library of Science) examines the potential of ursolic acid. The authors state:

Ursolic acid (UA), a pentacyclic triterpenoid carboxylic acid, is the major component of many plants including apples, basil, cranberries, peppermint, rosemary, oregano and prunes and has been reported to possess antioxidant and anti-tumor properties. These properties of UA have been attributed to its ability to suppress NF-κB (nuclear factor kappa B) activation. Since NF-κB…is known to regulate inflammatory genes, we hypothesized that UA might exhibit potent anti-inflammatory effects.”

They assessed the anti-inflammatory effects of ursolic acid through multiple markers including NF-κB in activated T cells, B cells and macrophages. They also tested the ability of UA to reduce inflammation in the mouse model of graft-versus-host disease. The effects were striking:

UA inhibited activation, proliferation and cytokine secretion in T cells, B cells and macrophages. UA inhibited mitogen-induced up-regulation of activation markers and co-stimulatory molecules in T and B cells…and suppressed the activation of immunoregulatory transcription factors NF-κB, NF-AT and AP-1 in lymphocytes. Treatment of cells with UA prior to allogenic transplantation significantly delayed induction of acute graft-versus-host disease in mice and also significantly reduced the serum levels of pro-inflammatory cytokines IL-6 and IFN-γ. UA treatment inhibited T cell activation…demonstrating its therapeutic utility as an anti-inflammatory agent.”

Transplantation specialists should note the ability of ursolic acid to delay acute graft-versus-host disease. The authors understate their conclusion:

“The present study describes the detailed mechanism of anti-inflammatory activity of UA. Further, UA may find application in the treatment of inflammatory disorders.”

The use of resveratrol and curcumin to reduce excessive B cell and T cell inflammatory activity came to light in a paper published earlier in Clinical & Experimental Immunology, The Journal of Translational Immunology. The authors note:

“The role of resveratrol and curcumin is well documented in cancer, inflammation, diabetes and various other diseases. However, their immunosuppressive action on T cells, B cells and macrophages is not well documented. In the present study, we have ascertained the effect of resveratrol and curcumin on T and B cells and macrophages.”

CD28 and CD80 are proteins found T cell and B cells respectively that participate in proinflammatory signaling. An important job of the cytokine IL-10 when produced by regulatory T cells is to keep inflammation in check…

“The most striking findings were that both resveratrol and curcumin suppressed the activity of T and B cells and macrophages, as evidenced by significant inhibition in proliferation, antibody production and lymphokine secretion. Interestingly, curcumin imparted immunosuppression by mainly down-regulating the expression of CD28 and CD80 and up-regulating CTLA-4. Resveratrol also functioned by decreasing the expression of CD28 and CD80, as well as by augmenting the production of interleukin (IL)-10.”

And evidence that curcumin downregulates B cell proinflammatory activity by reducing NF-κB expression is offered in a study published last year in the European Journal of Pharmacology. The authors observe:

“Overexpression of B lymphocyte stimulator (BLyS) is closely involved in the pathogenesis and progression of some autoimmune diseases. Curcumin, a pharmacologically safe agent, has been shown to possess potent anti-inflammatory properties.”

Their intent was to determine if curcumin decreases the activity of B lymphocyte stimulator. Their results are noteworthy:

“In this study, we report that curcumin inhibits the expression of BLyS and that a DNA-binding site for the transcriptional factor NF-κB in the BLyS promoter region is required for this regulation. Moreover, we find that curcumin reduces the DNA-binding activity of NF-κB to the BLyS promoter region and suppresses nuclear translocation of p65, suggesting that curcumin may suppress BLyS expression via negatively interfering with NF-κB signaling. These results suggest that curcumin may serve as a novel therapeutic agent in the treatment of autoimmune diseases by targeting BLyS.”

While interfering with inflammatory signaling is far from a comprehensive treatment strategy for Sjögren’s syndrome or any autoimmune disorder, the use of pharmacologically safe agents such as ursolic acid, curcumin and resveratrol deserve to be considered as part of the case management plan.

Autoimmunity is multi-causal. Another important aspect to evaluate in case management of  Sjögren’s syndrome, the role of sex steroid dysregulation, is presented in a paper just published in the Journal of Autoimmunity. It should be noted that that Sjögren’s syndrome has a female dominance of nine to one…

Estrogens seem to specifically protect secretory glandular acinar cells against apoptosis whereas lack of estrogens during menopause and climacterium specifically leads to increased apoptosis of the exocrine secretory cells.”

In other words, estrogens are necessary to sustain the viability of the cells of the salivary and lachrymal glands. Additionally, the androgen dihydrotestosterone (DHT) which is produced from adrenal DHEA (dehydroepiandrosterone) in women is important but vulnerable to disturbance:

“Male gonads produce testosterone and convert it in exocrine glands to dihydrotesterosterone (DHT), which is anti-apoptotic and protects against acinar cell apoptosis. Estrogen-deficient women need to produce dehydroepiandrosterone (DHEA) in the adrenal glands and convert it to DHT in exocrine glands in a complex and branching reaction network… Tailoring DHT in peripheral tissues is much more complex and vulnerable in women than in men. In SS the intracrine steroidogenic enzyme machinery is deranged. These endo-/intracrine changes impair acinar remodeling…The disarranged endo-/intracrine estrogen/androgen balance induces acinar cells to release microparticles and apoptotic bodies and to undergo apoptotis and/or anoikis.”

Most importantly, the breakdown particles of these degenerative changes become targets for B cells and T cells in autoimmunity:

“Membrane particles contain potential autoantigens recognized by T- (TCRs) and B-cell receptors (BCRs) and danger-associated molecular patterns (DAMPs) recognized by Toll-like receptors (TLRs). In membrane particles (or carrier-complexes) antigen/adjuvant complexes could stimulate professional antigen capturing, processing and presenting cells, which can initiate auto-inflammatory and autoimmune cascades, break the self-tolerance and finally lead to SS.”

Thus hormone dysregulation, including suboptimal estrogen stimulation and insufficient adrenal production of DHEA and subsequent conversion to DHA, can promote loss of glandular self-tolerance resulting in Sjögren’s syndrome. Stay tuned for forthcoming posts on other important aspects of case management of Sjögren’s syndrome and autoimmunity in general.

Leave a Reply