Most of the better known and more common forms of autoimmune disease are not all that age-related, though incidence for many of them ticks upwards with age as the immune system becomes ever more dysfunctional in later life. There are many more autoimmunities that are age-related, however, mostly comparatively poorly understood, and new ones are discovered on a fairly regular basis. It is fair to say that autoimmunity as a whole is poorly understood, however. The immune system is enormously complex, and it remains to be established as to how exactly it falls into the malfunctioning states that cause it to attack specific tissues, cells, and proteins that it should normally leave alone. It is unlikely that there is any one root cause, but the hope in the research community is that the broad range of quite different autoimmunities do in fact have commonalities, as is the case for cancer. Just as in cancer research, meaningful progress in the medical control of autoimmunity will likely hinge on identification and targeting of mechanisms shared by many or a majority of the diseases in this category.
One of the most promising approaches to autoimmunity is to bypass entirely the investigation of its mechanisms and just destroy the entire population of adult immune cells. The state-related data of the immune system, such as its memory, and including the errors that cause it to attack tissues rather than pathogens, is stored entirely in those cells. Wiping it clean and starting over has been shown to cure multiple sclerosis, for example. Unfortunately this is a fairly risky and damaging process at the moment, given the harsh nature of the high-dose immunosuppressants required, which makes it unsuitable for all but the most dangerous autoimmune conditions. One path forward is to produce better targeted cell-killing technologies, therapies that lack side-effects, and that is certainly a going concern in the biotechnology community. Such a side-effect-free therapy would still leave the patient without a functioning immune system for a period of time, however, which would add considerably to the support needed to make such a treatment safe enough for widespread use, especially in older people.
What if a much smaller population of errant immune cells could be identified and selectively destroyed, however? The autoimmunity could be suppressed or removed without having to destroy the entire immune system, and that could possibly be achieved to a good enough degree with existing technologies. That is the promise offered by research into age-associated B cells, a class of dysfunctional immune cell discovered not so many years ago. In the research noted here, an important role for these cells appears to be confirmed for a range of classes of autoimmunity. This seems to me to be an noteworthy step forward in the field, and opens a number of paths towards forms of effective treatment for autoimmune conditions.
Researchers have identified a trigger for autoimmune diseases such as lupus, Crohn’s disease and multiple sclerosis. The findings help explain why women suffer autoimmune disease more frequently than men, and suggest a therapeutic target to prevent autoimmune disease in humans. “Our findings confirm that Age-associated B Cells (ABCs) drive autoimmune disease. We demonstrated that the transcription factor T-bet inside B cells causes ABCs to develop. When we deleted T-bet inside B cells, mice prone to develop autoimmune disease remained healthy. We believe the same process occurs in humans with autoimmune disease, more often in elderly women.”
B cells are important players in autoimmune disease. The research team previously identified a subset of B cells that accumulate in autoimmune patients, autoimmune and elderly female mice. They named the cells Age-associated B cells, or ABCs. Subsequent research showed that the transcription factor T-bet plays a crucial role in the appearance of ABC. Transcription factors bind to DNA inside cells and drive the expression of one or several genes. Researchers believe that T-bet appears inside cells when a combination of receptors on B-cell surfaces – TLR7, Interferon-gamma and the B-cell receptor – are stimulated.
Through breeding and genetic techniques the research team eliminated the ability of autoimmune-prone mice to express T-bet inside their B cells. As a result, ABCs did not appear and the mice remained healthy. Kidney damage appeared in 80 percent of mice with T-bet in the B cells and in only 20 percent of T-bet-deficient mice. Seventy-five percent of mice with T-bet in their B cells died by 12 months, while 90 percent of T-bet-deficient mice survived 12 months. “Our findings for the first time show that ABCs are not only associated with autoimmune disease, but actually drive it.”
B cells are known to be involved in different aspects of autoimmune diseases and may contribute in a number of ways including the secretion of autoantibodies, processing and presentation of autoantigen to T cells, and production of inflammatory cytokines. Therefore, B cells are promising targets for treatment of autoimmune diseases. Indeed, this idea has been put into practice and B cell depletion therapy has been tested for multiple autoimmune diseases. It is not yet known why B cell depletion is effective for some but not all diseases and for some but not all patients with a particular malady. One possibility is that the depletion therapies might not affect all B cell subsets equally well and different diseases, or different patients, might have involvements of different B cell subsets.
A novel subset of B cells named age-associated B cells (ABCs) has recently been identified by others and ourselves. Unlike other B cells, ABCs express high levels of CD11c and the transcription factor T-bet. T-bet was subsequently demonstrated to be necessary and sufficient for the appearance of this subset, and triggering of the B cell antigen receptor (BCR), IFN-γ receptor (IFN-γR), and TLR7 on B cells induces high levels of T-bet expression. Our previous data demonstrated that T-bet+ ABCs appear in autoimmune patients and in autoimmune-prone mice. These cells produce high amounts of autoantibodies upon stimulation in vitro, suggesting that they are major precursors of autoantibody-secreting cells.
Moreover, our recent findings indicate that ABCs are very potent antigen-presenting cells and therefore might participate in autoimmune responses by presenting self-antigen to autoreactive T cells. In agreement with our findings, a recent study demonstrated elevated levels of T-bet expression in B cells obtained from peripheral blood mononuclear cells of lupus patients when compared with healthy donors, suggesting that T-bet expression in B cells may be critical for the development of lupus in humans. Others have reported that T-bet-expressing B cells are associated with Crohn’s disease activity, and an increased expression of T-bet in B cells was found in a patient with MS and celiac disease, altogether suggesting an important role for T-bet-expressing B cells in human autoimmunity.
Therefore, we hypothesized that ablation of ABCs will prevent or delay the development of lupus-like autoimmunity. We tested this hypothesis by conditionally deleting T-bet from B cells in a mouse model of lupus. Our data demonstrate that this deletion leads to reduced kidney pathology, prolonged survival, and delayed appearance of autoantibodies in these mice. Moreover, our data suggest that T-bet expression in B cells is required for the rapid formation of spontaneous germinal centers that develop without purposeful immunization or infection during such autoimmune responses. The results indicate a critical role for T-bet expression in B cells for the generation of efficient autoimmune responses and the development of lupus-like autoimmunity, and suggest that specific targeting of T-bet+ B cells might be a useful therapy for some autoimmune diseases.