This is the second of three lengthily posts involving autoimmune diseases and lymphoma. In the first post I focused on a particular autoimmune disease, Lupus erythematosus, its genetic causes and new therapies intended to address it. This Part II post is concerned with the association between Lupus and other autoimmune diseases with lymphoma, what this association is telling us, and the key role of inflammation. Further, I discuss the key role of NF-kappaB), a cell nuclear factor, in autoimmune-related inflammation and possibly in the transition to lymphoma.
Autoimmune diseases, inflammation and lymphoma
It has long been observed that certain autoimmune diseases convey an increased risk of malignant lymphomas, but the nature and cause of this risk seemed unclear. A 2006 review study publication by a Swedish team cast some light on the situation: Malignant Lymphomas in Autoimmunity and Inflammation: A Review of Risks, Risk Factors, and Lymphoma Characteristics . “Recent results clearly indicate an association between severity of chronic inflammation and lymphoma risk in RA (rheumatoid arthritis) and SjÃ¶gren’s syndrome. Thus, the average risk of lymphoma in RA may be composed of a markedly increased risk in those with most severe disease and little or no increase in those with mild or moderate disease.” – “Furthermore, RA, SjÃ¶gren’s syndrome, systemic lupus erythematosus, and possibly celiac disease may share an association with risk of diffuse large B-cell lymphoma, in addition to well-established links of SjÃ¶gren’s syndrome with risk of mucosa-associated lymphoid tissue lymphoma and of celiac disease with risk of small intestinal lymphoma(ref).”
Several parallel and subsequent reports confirm and further clarify the association, such as this study relating autoimmune diseases to WaldenstrÃ¶m macroglobulinemia (WM), a non-Hodgkin lymphoma subtype. That study looked at histories of 4 million US veterans, of which 361 were identified to be patients with WM. “In the largest investigation of WM risk factors to date, we found a 2- to 3-fold elevated risk of WM in persons with a personal history of autoimmune diseases with autoantibodies – (ref).” These two (ref)(ref) 2009 reports review epidemiological studies that relate autoimmune diseases to lymphomas and other pathologies.
It seems that presence of intense inflammation is a predictor of susceptibility to lymphoma in patients with an autoimmune disease, and that control of the inflammation can lessen the probability of a lymphoma emerging. This report concludes “Risk of lymphoma is substantially increased in a subset of patients with RA, those with very severe disease. High inflammatory activity, rather than its treatment, is a major risk determinant.” Another Swedish report based on the same data looked at the impact of long-term anti-inflammatory treatment of RA patients with steroids on susceptibility to lymphoma. The study compared a population of 378 individuals with both RA and associated lymphoma with a matched population of individuals with RA but without lymphoma. The study concluded that “Increased duration of corticosteroid use (more than 2 years) was associated with a reduced risk of lymphoma (particularly large B-cell lymphoma) in RA patients(ref).” While the result is interesting, prolonged use of a powerful steroid like prednisone may not be a good thing. John Hopkins medical editors caution “– that any benefit of prolonged steroid treatment on the prevention of lymphoma must be balanced against known detrimental side effects (i.e. ischemic heart disease, insulin resistance, osteoporosis, etc…) that are more common and may result in greater group morbidity and mortality than lymphoma(ref).
Lymphoma and lupus are both diseases that involve B-cell pathologies and control of inflammation via prednisone is a common feature of the conventional treatment approaches for both. This report - The treatment of lymphoma complicating autoimmune disease: two birds with one stone? – looks at the vexing issue of how best to treat a non-Hodgkin lymphoma in the context of an auto-immune disease and discusses using R-CHOP as a common protocol addressing both disease conditions. R-CHOP stands for a chemotherapy regimen of five drugs used to treat aggressive non-Hodgkin lymphomas(ref).
What are autoimmune diseases at a cellular level? Different autoimmune diseases correspond to different immune system abnormalities, and these are in most cases quite complex and only partially understood. For example, in the case of SLE: “Although tissue-bound antigen-antibody complexes are the principal effectors of this inflammatory process, a fundamental disorder of the immune system that permits the inappropriate production of autoantibodies exists at the cellular level. It is currently held that T-lymphocyte effector dysfunctions contribute to this altered immune response in SLE. Indeed, diverse T-cell dysfunctions have been well described in SLE. Among these are (a) exaggerated CD4 T-helper (Th) activity; (b) diminished CD8 T-cytotoxic/regulatory (Tc) function; (c) imbalanced production of Th1 and Th2 cytokines, and (d) reduced proliferative responses to antigens/mitogens. These diverse T-cell dysfunctions lead to an imbalance between helper and cytotoxic/regulatory functions that promote B-cell proliferation, differentiation and antibody production. Due to the loss of effective Tc regulatory feedback to B cells, forbidden B-cell clones can produce autoantibodies directed against an array of intra- and extracellular autoantigens(ref).”
Role of NF-kappaB
Given that rampant inflammation plays such an important role in autoimmune diseases, in the genesis of autoimmune-related lymphoma, and in lymphomas themselves, what can be said about the process that leads to such inflammation? I look at that issue here from a particular vantage point, examining the role nuclear factor NF-kappaB in the inflammatory process of an autoimmune disease.
(As background, expression of NF-kappaB plays an important role in the Programmed Epigenomic Changes theory of aging covered in my treatise. NF-kappaB is also discussed in several previous blog entries including Updates on NF-kappaB, DHMEQ, A further update on NF-kappaB, On the TRAIL of a selective cancer treatment, Histone acetylase and deacetylase inhibitors, Spices of life, Anti-inflammatory effects of the hormone alpha-MSH, and More on DHMEQ and a no-no mind bender. )
For purposes of this post, I draw heavily from a 2006 report A role for transcription factor NF-kappaB in autoimmunity: possible interactions of genes, sex, and the immune response. “Gene and hormone alterations of the NF-kappaB signaling cascade provide a unifying hypothesis to explain the wide-ranging human and murine autoimmune disease phenotypes regulated by NF-kappaB, including cytokine balance, antigen presentation, lymphoid development, and lymphoid repertoire selection by apoptosis.” The discussion in this paper is complex but worth following for readers seriously interested in grasping what is going on. In simplified terms some of the main points are:
· Most autoimmune diseases including lupus are expressed much more frequently by females than by males, “– women account for 80% of cases.” — “hormonal shifts in pregnancy, menopause, and aging are associated with fluctuations in the course of autoimmune disease(ref).”
· “NF-kappaB appears to be a central player in several autoimmune diseases, according to recent studies of genetic defects in autoreactive lymphoid cells (the immune cell types responsible for autoimmunity) in both murine models of autoimmunity and humans with diverse forms of autoimmunity.” “– in autoimmune diseases “both genes and sex hormones may exert their effects through the same general mechanism, dysregulation of transcription factor NF-kappaB –(ref).”
· “Although the genes altering NF-kappaB appear to vary in different autoimmune diseases, usually decreased NF-kappaB activity in response to select cell surface cytokines is commonly observed.” — “In a normal immune cell in the periphery, exposure to TNF (tumor necrosis factor) triggers a complex pathway of NF-kappaB activation that culminates in an active NF-kappaB dimer entering the nucleus, i.e., the p50/p65 complex. This NF-kappaB complex ensures that the cell will survive(ref).” It does this by activating genes that protect the cell from apoptosis. “As shown, studies in autoimmunity have identified mutations and functional blocks in the NF-kappaB signaling pathway in autoimmune disease. These mutations alter the autoreactive T cells signaling due to disruptions in NF-kappaB activation.” In the presence of such a mutation there is no NF-kappaB activation there is no protection against apoptosis induced by TNF and the cell dies. “NF-kappaB controls cell death (apoptosis) and life decisions in immune cells in the periphery. If the NF-kappaB pathway is intact in the periphery, activated NF-kappaB enters the nucleus and results in the transcription of genes for survival. If the NF-kappaB pathway via is blocked, the cell will die instead with TNF exposure. TNF is essential in the peripheral in maintaining cell life and death decisions and control of T cell populations(ref).”
· “In lupus, activation of NF-kappaB signaling is attenuated in T cells due to the absence of the p65 appearance in the nucleus, one of the NF-kappaB subunits that binds to DNA .This is compounded in lupus by a polymorphism in TNF receptor 2, a version of the TNF receptor restricted to activated CD8 T cells. This mutation affects TNF-induced apoptosis by decreased NF-kappaB signaling and thus the set point for death(ref).”
At this point I flag what appears to be a paradox: 1. The above says the pathology underlying lupus and several other autoimmune diseases is connected with attenuated NF-kappaB signaling and insufficient translocation of the p65 subunit into the nucleus in immune cells, 2. Glucocorticoids like prednisone (used for treating lupus, other autoimmune diseases and many forms of lymphoma) work by inhibiting the nuclear transport of NF-kappaB (ref). If the initial problem is too much inhibition, how does further inhibition help as a key step in controlling inflammation? Clearly, there are many other signaling pathways involved besides NF-kappaB.
Implications for the anti-aging firewalls regimen In the light of the above, a question arises as to the roles of some of the substances in the firewall regimen for individuals who have inflammatory autoimmune diseases. I am thinking of substances that are at the same time anti-inflammatories, anti-oxidants, pro-apoptosis agents in cancers and promoters/inhibitors of NF-kappaB. Green tea extract, curcumin and resveratrol are examples. What is the net effect of taking such supplements on individuals having an autoimmune disease?
The answer may vary by disease and substance but curcumin may offer an example. “Recent studies have shown that curcumin ameliorates multiple sclerosis, rheumatoid arthritis, psoriasis, and inflammatory bowel disease in human or animal models. Curcumin inhibits these autoimmune diseases by regulating inflammatory cytokines such as IL-1beta, IL-6, IL-12, TNF-alpha and IFN-gamma and associated JAK-STAT, AP-1, and NF-kappaB signaling pathways in immune cells(ref).” “Traditionally known for its antiinflammatory effects, curcumin has been shown in the last two decades to be a potent immunomodulatory agent that can modulate the activation of T cells, B cells, macrophages, neutrophils, natural killer cells, and dendritic cells. Curcumin can also downregulate the expression of various proinflammatory cytokines including TNF, IL-1, IL-2, IL-6, IL-8, IL-12, and chemokines, most likely through inactivation of the transcription factor NF-kappaB(ref).” See also these additional references with respect to the potential roles of curcumin for treating autoimmune diseases. And such references also exist for the potential role of curcumin in lymphoma prevention, such as “Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1, c-myc, bcl-XL, NF-kappa B, and p53”. So it appears that for curcumin at least, its impact on autoimmune diseases is likely to be positive. A similar conclusion appears to be the case for green tea(ref)(ref)(ref)(ref) and resveratrol(ref)(ref)(ref) and may also be true for several other of the firewall substances. Again, please see the medical disclaimer in the previous post.
Inhibition of the expression of NF-kappaB is a general strategy for retarding aging according to the 14th theory of aging covered in my treatise Programmed Epigenomic Changes. There appears to be a solid research basis for that strategy. In fact, 36 substances in my combined anti-aging supplement regimen inhibit the expression of NF-kappaB.
This Part II post has focused on the relationship of autoimmune diseases to lymphoma, the critical role of inflammation in that relationship, the roles that TNF, NF-kappaB and cell death play in autoimmune diseases, and the potential role a few of the anti-aging firewall substances can play in controlling autoimmune diseases. A final Part III post will focus on lymphomas, their classifications and conventional and emerging therapies for lymphomas.