T Cell Repertoire Dynamics
during Pregnancy in Multiple Sclerosis
Ramien C, Yusko EC, Engler JB, Gamradt S, Patas K, Schweingruber N, Willing A, Rosenkranz SC, Diemert A, Harrison A, Vignali M, Sanders C, Robins HS, Tolosa E, Heesen C, Arck PC, Scheffold A, Chan K, Emerson RO, Friese MA, Gold SM
Multiple sclerosis disease activity is reduced by up to 80% during pregnancy, but then can rebound in the months after delivery. This paper describes changes in the immune system in women with MS during pregnancy. The authors identified certain clones of immune cells (T cells) that were reduced in numbers in the blood during pregnancy but then increased in numbers after delivery. Increased clone numbers was associated with relapses of disease. Most interestingly, the T cell clones were “private,” that is unique to each woman, suggesting different patterns of disease in different individuals. Also of importance, the clones did not respond to myelin proteins and only rarely to viral proteins. This paper is the first to describe fluctuations in clones of immune cells during pregnancy and in post-pregnancy relapses. Learning how these clones are regulated, and identifying what stimulates them would be a breakthrough in understanding the MS disease process.
1. Pregnancy reduces disease activity in women with MS, up to 80% by the third trimester.
2. Hormonal changes contribute to this disease suppression, but administration of hormones elevated during pregnancy to non-pregnant women does not result in the degree of disease suppression noted during pregnancy. Thus, additional factors must be involved in the protective effects of pregnancy.
3. The researchers studied 11 women with MS during pregnancy and 12 matched controls of pregnant women without MS. Blood was obtained during each of the three trimesters of pregnancy and at three months after delivery.
4. Immune cells called T cells were isolated from blood and their molecular structures studied. T cells interact, and are stimulated to multiply by specific fragments of proteins called antigens. The interactions between a T cell and its specific antigen occurs via protein-recognition sites on T-cell surfaces called antigen receptors. Each T cell has a unique antigen receptor, able to recognize a unique protein fragment or antigen.
5. The scientists found that certain T cells were selectively increased in the blood of women with MS and in healthy controls. Overall numbers of such T cells or T cell clones were the same in both groups of women.
6. During pregnancy, however, there was a significant reduction in numbers of specific T cell clones in the blood of women with MS, but not in the blood of women without MS. Numbers of particular T cell clones continued to decline during pregnancy, reaching a low point during the third trimester. Overall numbers of T cells were the same in both groups of women.
7. T cells can be divided into two major groups based upon their expression of certain proteins on their cells surfaces. The two groups are called CD4+ cells and CD8+ cells. As a very broad characterization, CD4+ cells are involved in helping other immune cells respond to antigens while CD8+ T cells are involved in killing and eliminating other cells, usually infected cells or malignant cells.
8. Both major groups of T cell clones were reduced in pregnant women with MS but not in controls. Neither were reductions in clonal numbers noted in healthy women that were not pregnant. The clones that were reduced in pregnant women with MS but not controls had been exposed to particular antigens in the past, as opposed to “virgin” clones that had not seen their particular protein fragments in the past.
9. Over 100 T cell clones were identified in the blood of both groups of women and numbers of these clones studied during pregnancy. Only in pregnant women with MS were their reductions in numbers of cells of each of the clones, dropping increasingly as the pregnancy progressed. The antigen receptors on the cell surfaces of these clones were “private,” that is unique to each individual.
10. Following the end of pregnancy certain clones that had been greatly reduced in number began to greatly increase in numbers. Again, this was not noted in control women. Increases in clone numbers were associated with clinical relapses in several women with MS.
11. Clones were tested for their responses to proteins of myelin and to proteins of the Epstein-Barr virus, a virus associated with increased risk for developing MS. None of the clones that increased in numbers after delivery and were associated with relapses responded to myelin proteins. Only three of the over 100 clones tested responded to the viral proteins.
12. This paper is important not only for its unique insights into changes in the immune system that occur with pregnancy, but also for the many questions it raises regarding the nature of the antigens that stimulate the clones after pregnancy, how these clones are “down-regulated” during pregnancy, and what factors allow these clones to “escape” control after pregnancy. Answering these questions could provide critical information on the causes of MS relapses and how best to prevent them.
One of the many mysteries regarding the course of disease in MS is the effect of pregnancy on disease activity. In contrast to other autoimmune diseases such as systemic lupus erythematosis where pregnancy worsens the disease, pregnancy has a quieting effect on MS, reducing relapses by as much as 80%, a better response than seen with some of the disease-modifying therapies. Another mystery of MS is why there is a greatly increased risk of a major flare of disease weeks to months after the pregnancy. Many studies have implicated certain hormones that increase during pregnancy as factors in disease control and relapse, but administration of such hormones have, at best, had only modest effects on disease course.
Studies of immune cells over the past several decades have shown that particular populations of cells, especially T cells, are clonally increased in the blood and brains of persons with MS. In other words, the variety of T cells in MS is not evenly distributed. Rather specific T cells are selectively expanded. These are called T cell clones. Such clones are present in both the blood and central nervous systems of persons with MS, and much effort has been put forth trying to determine what stimulates these clones and how do they relate to the disease process. Some studies showed these clones responded to brain proteins. Other studies showed that some clones responded proteins of the Epstein-Barr virus. However, results have varied greatly among different labs and to date there are no definitive data implicating either a particular myelin protein or a particular virus as the cause of immune stimulation in MS.
The paper by Yusko and colleagues summarized above is a major advance in our understanding of disease processes in MS, in particular MS during pregnancy. The authors show that there are preferentially expanded populations of T cells (T cell clones) in both women with MS and those without MS, but that during pregnancy some of these clones are repressed, but only in women with MS. The repression increases with duration of pregnancy, being most noted in the 3rd trimester. However, following delivery, some of these clones rapidly increase in number and are associated with the appearance of clinical relapses. The clones identified are unique to each individual woman, indicating a great diversity in patterns of immune responses in persons with MS. In addition, none of the clones responded to myelin antigens and only three out of more than 100 responded to a protein of Epstein-Barr virus. It remains a mystery as to what regulates numbers of clones during MS-related pregnancies, what stimulates these clones after delivery, and how do these expanded clones result in the appearance of MS flares. Learning answers to these questions may shed important light on two fundamental questions in MS: Since the clones from women with MS were “private”, that is unique to each woman, does that mean that MS is not a disease with a uniform cause but a syndrome, such as pneumonia, with multiple causes and pathways to myelin destruction in different individuals? Is there only one antigen responsible for stimulating the immune system to attack the brain, or are there multiple antigens involved? And finally, once antigens are known, can one induce immune tolerance to them, such that the immune systems of persons with MS no longer respond to them, resulting in a decrease, and possibly a halt, to disease activity?