Autoimmuniry, 1992, Vol. 13. pp. 31 1-319 Reprints available directly from the publisher Photocopying permitted by license only

0 1992 Hanvood Academic Publishers GmbH Printed in the United Kingdom

CELLULAR IMMUNE MECHANISMS IN CHRONIC AUTOIMMUNE THROMBOCYTOPENIC PURPURA (ATP) JOHN W. SEMPLE* and JOHN FREEDMAN Division of Hematology, St Michael’s Hospital and the Departments of Pharmacology* and Medicine, University of Toronto, Toronto. Ontario, Canada Autoimmunity Downloaded from informahealthcare.com by Freie Universitaet Berlin on 12/04/14 For personal use only.

(Received January 27,1992; in final form June 9,1992) Chronic autoimmune thrombocytopenic purpura (ATP) is a common autoimmune-mediated bleeding disease in which autoantibodies are directed against platelets, resulting in their enhanced Fc-mediated destruction by macrophages in the spleen. While there has been extensive studies relating to the autoantibodies in this autoimmune disorder, relatively few have dealt with cell-mediated immunoregulation of the anti-platelet autoantibody response. Nonetheless, there is accumulating evidence that suggests the production of these anti-platelet autoantibodies is under the influence of several abnormal lymphocyte-mediated mechanisms, i.e. enhanced anti-platelet T helper cell activity with concomitant reduced T suppressor cell activity. This review focuses on these cellular events and presents a working model which attempts to explain their close interrelationships. KEY WORDS: Autoimmunity, thrombocytopenia, platelets, immunoregulation, T helper cells, NK cells.

INTRODUCTION The initiation of a humoral immune response to a foreign antigen is a complex biologic process involving the interaction of many cell types and their secreted products. The response occurs when the antigen, e.g. a cell surface glycoprotein, first interacts with an antigen presenting cell (APC), i.e. a major histocompatibility complex (MHC) class I1 positive macrophage or dendritic cell. Subsequently, the APC internalizes and “processes” the antigen by proteolysis into smaller antigenic peptides and reexpresses and presents them on its membrane, in association with molecules encoded by the MHC, to antigenspecific T helper cells’32.The T helper cells, in turn, become activated by signals passed via their T cell receptor (TcR) complex, proliferate and secrete cytokines such as interleukin-2 (IL-2) and interleukin-6 (IL-6). These events subsequently stimulate antigenprimed B cells to produce and secrete antibodies. T helper cells are critical in determining whether antibodies are produced against the foreign antigen and finely control the response by activating regulatory events such as suppressor T cell activation and/or secretion of soluble cytokines. Any defect in or abnor-

Address correspondence to: Dr John W. Semple, Dept. of Immunohematology. St Michael’s Hospital, 30 Bond St, Toronto, Ontario, Canada, MSB IW8, Phone: (416) 864-5534; FAX: (416) 864-5693.

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ma1 stimulation of antigen-specific T helper cells can thus alter the magnitude of the immune response. Immunological tolerance is the acquisition of unresponsiveness to self antigens and is essential for the preservation of the host3. T cell tolerance can be induced by either clonal deletion of self-reactive T cells centrally within the thymus4 or by T cells being rendered anergic by specific and non-specific mechanisms’ in the extrathymic periphery. Autoimmune diseases result from the failure of normal self tolerance mechanisms; these diseases affect 5-7% of the population, often leading to severe disability and chronic illness6. Although the mechanisms of self-tolerance are being elucidated with respect to the development of the T cell repertoire in the thymus”, little is as yet known about how self tolerance is established for extrathymic self molecules. The breakdown of self tolerance may be the result of a number of non-mutually exclusive mechanisms, e.g. either abnormal numbers of self reactive T cells, the lack of active extrathymic peripheral suppressive mechanisms, and/or environmental stimuli which can mimic self (antigenic mimicry). Chronic autoimmune thrombocytopenic purpura (ATP) is a common haematologic bleeding disorder in which platelets are targeted for autoantibodymediated destruction. The diseases is characterized by thrombocytopenia due to increased platelet destruction, increased numbers of megakaryocytes in the bone marrow, absence of splenomegaly, and plateletassociated immunoglobulins (IgG in particular) and/or

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C37-y. Chronic ATP most often occurs in adults, is found 3-4 times more frequently in women than in men, and is persistent, often lasting years’”. The prevalence of ATP has been estimated at 1 per 20,000”. The thrombocytopenia and clinical consequences of chronic ATP result primarily from an Fc receptor-mediated phagocytosis of autoantibodycoated platelets by the monocytes/macrophages of the reticuloendothelial system, particularly in the spleen 12.13 Chronic ATP may be found associated with a wide variety of autoimmune diseases in a patient and there is a particular interrelationship with systemic lupus erythematosus (SLE), since approximately 10% of patients initially diagnosed with chronic ATP go on to develop SLE’4-’6,’7.Currently, the treatment for chronic ATP is palliative, and focuses on non-specifically reducing anti-platelet autoantibody production. Corticosteroid treatment is the usual first line therapy and for those who are resistant to steroids, splenectomy or more potent immunosuppression regimes, such as azathioprine and cyclophosphamide, are used. Other therapies which have been applied include danazol, high dose intravenous IgG, plasmapheresis, vincristine, vinblastine, cyclosporin-A, a-interferon, and ascorbic acid. The majority of immunological studies in chronic ATP have attempted to characterize serum anti-platelet autoantibodies while relatively few have been devoted to cellular immune function. This review will focus on the cellular immunoregulatory mechanisms in patients with chronic ATP and attempt to persuade the reader that defects in this arm of the immune response may be important in enhancing anti-platelet autoantibody production. PLATELET-ASSOCIATED AUTOANTIBODIES The nature and specificity of anti-platelet autoantibodies in ATP has been extensively studied and reviewed7-Y.i X-23 and are beyond the scope of this review. However, recent developments in mapping platelet-associated epitopes recognized by autoantibodies deserve comment. Most of the autoantigenic targets on platelet membranes are thought to be “public” antigens shared by normal platelet^'^. Various platelet membrane glycoproteins (CPs) have been reported to contain epitopes for anti-platelet autoantibodies. The best characterized platelet membrane GPs are GPIIb-IIIa (fibrinogen and fibronectin receptor) and GPIb-IX (von Willebrand receptor) and most of the epitopes recognized by autoantibodies are found on these platelet GPs, particularly GPIlb-IIIa2S.Recently, Fujisawa et al.?‘, using a series of in v i t m generated GPIIIa peptides, have demonstrated that approximately 40% of patients with

chronic ATP have plasma anti-GPIIb-IIIa autoantibodies with specificity for the carboxy terminal region within the cytoplasmic domain of the IIIa chain (amino acid residues 721-762). Since the carboxy terminus of G P IIIa may not be available for antibody binding in intact platelets under normal physiologic conditions, they subsequently compared the specificities of platelet-associated and plasma derived antibodies from patients with chronic ATP. They showed that the antibodies eluted directly from patient’s platelets had different specificities than the carboxy-terminal specific antibodies derived from the plasma”. Interestingly, those patients who had carboxy-terminal specific plasma autoantibodies also had particularly severe disease2’. Thus, these studies demonstrate that autoantibodies against G P IIIa react with multiple regions of the protein and suggest that the anti-platelet immune response may be antigen driven and not the result of antigenic mimicry2’. Other investigators have found that a 50 kD chymotryptic fragment of the GPIIIa chain (corresponding to its cysteine-rich region, amino acid residues 427-654) was recognized by autoantibodies in 58% of patients with ATP”. Based upon these studies, it is becoming evident that specific regions in GPIIb-IIIa are primary targets for autoantibody recognition in chronic ATP. Whether T cell epitopes are also found in the G P IIb-IIIa molecule and, more importantly, whether G P IIb-IIIa is the primary autoantigenic stimulus for autoantibody production in chronic ATP is unknown at present. Preliminary results from our laboratory demonstrate that purified G P IIb-I1Ia from normal platelets can stimulate T helper cells from patients with ATP to secrete IL-2 which can mediate the in vitro production of platelet specific autoantibodies by B lymphocytes. Nonetheless, it is also possible that other molecules, either associated with platelets (e.g. G P Ib-IX) or not, may be involved in the initiation and stimulation of the anti-platelet autoantibody response in ATP. GENETIC INFLUENCES Certain HLA molecules are associated with autoimmune diseases and may predispose the host to autoimmunity‘. This predisposition may be due in part, to how polymorphic HLA molecules present antigens to autoreactive T helper cells. For certain autoimmune diseases, it has been possible to identify short stretches of amino acids within the polymorphic regions of HLA molecules which play a major role in disease susceptibility and/or resistance”-”. Chronic ATP has been reported to be associated with HLADR2’j and also class I HLA molecules (HLA A28, B8 and B 12)”~”. Others, however, have found little or no HLA association with ATP’7. These inconsistencies may be, in part, due to the fact that for a given popu-

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lation of patients with a diagnoses of chronic ATP, a significant patient heterogeneity can exist which will affect genetic marker studies. Further in depth studies with large patient populations will be needed to ascertain which HLA molecules (if any) may be associated with ATP. Chronic ATP tends to be a sporadic autoimmune disorder since familial occurrence is rare3*. A variety of immunologic abnormalities have, however, been found in first degree relatives of patients with ATP''." which lends credence to the hypothesis that there is a genetic component associated with chronic ATP. B LYMPHOCYTES Abnormal production of autoantibodies in autoimmune states may be due to intrinsic defects within B lymphocyte populations or aberrant mechanisms which influence B cells directly. These may include hyperactivity or enhanced susceptibility of B cells to external stimuli, increased antigenic loads and/or enhanced T cell-mediated immunostimulation. Abnormalities in B lymphocytes have been reported in a number of autoimmune however, relatively little work has been devoted to directly studying B cells in chronic ATP. Mizutani et al.4' have recently shown a significant increase in circulating and splenic CD5 positive (CDS') B lymphocytes in patients with ATP and correlated this increase with their ability to produce antiplatelet antibodies in vitro. CD5' B cells have been shown to be increased and responsible for autoantibody production in different autoimmune diseases"'~". Nonetheless, whether CD5' B cells are responsible for the development of autoimmunity is still an open question". We have shown elevated levels of circulating CD19' B cells, of which CD5' B cells are a subset, in patients with ATP44 which correlate to Mizutani's observations. On the other hand, patients with ATP have expanded clonal populations of B cells based on K/A flow cytometric analysis and southern blot analysis but these clonal expansions are not restricted to CD5' B cell subpopulations". In general, these studies suggest that abnormalities do exist within the B cell compartment of patients with ATP, however, it remains to be determined which B cell subset(s) is primarily responsible for anti-platelet autoantibody production. Using a T:B lymphocyte co-culture system, in which titrations of T cells were added to B lymphocytes, Trent et al." demonstrated enhanced IgG production in a patient with ATP and concluded that antiplatelet autoantibody production may be the result of either B cell hyper-responsiveness and/or a T suppressor cell defect. To expand these findings, Figure 1 shows that enriched CD19' B cell populations from

patients with ATP can be stimulated with autologous CD4' T helper cells and platelets in vitro to produce greater amounts of platelet-specific autoantibodies than normal B cells4'. Thus, B cells from patients with ATP are responsive to platelet-driven T cell help and anti-platelet autoantibody production in patients with chronic ATP may be regulated and enhanced by a T cell defect. T LYMPHOCYTES Over the past 20 years, there have been a number of studies which have described T cell defects and attempted to elucidate their role in the pathogenesis of ATP. These studies have produced conflicting results which has made it difficult to realize the exact role that T cells may play in the disease. However, certain results have emerged over the years which implicate T cells as potential initiators of autoantibody production in ATP and suggest that some of the T cell defects in chronic ATP are similar to those seen in other autoimmune states such as SLE and rheumatoid arthritis.

Phenotypic characterizations Quantitative phenotypic analyses from various labora-

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Figure 1 Anti-platelet reactivity of IgC immunoglobulins produced in B cell stimulation assays. Enriched T and B (4: I ; T:B) cells from patients with ATP were incubated with normal platelets for 10 days at 37°C and the supernatants were harvested and tested for reactivity against platelet membranes in an ELISA. Results are expressed as O D units (405 nm). ATP (pit+), ATP patients showing plateletinduced IL-2 production; ATP (plt-), ATP patients with no IL-2 activity; NIT, non-immune thrombocytopenic patients; NTID, nonthrombocytopenic immune disease.

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tories have demonstrated a decrease in CD8' T suppressor lymphocyte^^'*^^ and CD4+/CD8+ratios in patients with chronic ATP. Others, however, have reported normal CD4'/CD8' ratio^^*.^', increases in CD4' and CD8' T lymphocyte^^'^^^, increased numbers of double-positive CD4'CD8+ immature T cellss4, and an increase in activated HLA-DR' T ~ e l l in s ~ patients with ATP which may reflect antigenic stimulation of autoimmune T cells by platelet antigens. The lack of consistency in the phenotypic quantitative studies could be due to differing clinical status of patients studied, the different techniques used, or to consequences of various therapies the patients may have been receiving. Specific subsets of CD4' and of CD8' T cells have been examined in patients with ATP by dual-label flow ~ y t o m e t r y ~The ~ . CD45R-specific 2H4 monoclonal antibody in conjunction with anti-CD4 defines a subset of T cells termed T suppressor-inducer cells (Tsi). Tsi cells are responsible for stimulating the production of CD8' suppressor T cells to down-regulate an immune response, or to tolerize the immune system to self antigen^^^,^^. A decrease in the numbers of Tsi cells has been reported in a number of autoimmune diseases, such as SLE, rheumatoid arthritis and multiple s ~ l e r o s i s ~ Women ~ - ~ ~ . with active ATP have a significant reduction in circulating CD4TD45R' Tsi cells whereas those women in remission have normal numbers". Reductions in CD4' Tsi cells in patients with ATP have also been demonstrated using the Leu8' monoclonal antibody44. Because of the specificity differences between Leu 8 and 2H4 however, it cannot be ascertained whether these T cell subpopulations are the same. Furthermore, it should be noted that lymphocyte phenotypic studies, while useful with respect to quantifying lymphocyte subsets, may not inform regarding functional and pathophysiologic significance. A perturbation of the normal clonal T cell receptor balance has been reported in a number of autoimmune Such studies have shown restricted heterogeneity of TcR V a , V P and V yand V6gene usage. Posnett et dh7 used a panel of three monoclonal antiTcR antibodies specific for different variable region determinants to study discrete populations of peripheral blood T cells in patients with autoimmune diseases including ATP. Although most of the patients were found to have normal expression of the TcR proteins studied and no evident disease associations, several did have elevated percentages of CD8' T cells expressing the OT145' phenotype which corresponds to usage of a particular P-chain V gene". These studies, although using a limited number of antibodies, indicate that a small number of patients with ATP have abnormal expression of TcR gene products. As more mAb to TcR V gene determinants become available, further studies of this type to show possible cau-

sal relationships between expanded populations of T cells and the autoimmune disease will be necessary. Functional studies

One of the earliest studies which demonstrated abnormal ~ ~cellular ~ ~ immune reactivity in ATP was performed by Piessens et who demonstrated that peripheral blood lymphocytes from patients with ATP undergo increased blastogenic transformation when stimulated with autologous platelets. Subsequently, McMillan et a1.6" demonstrated that concanavalin A-stimulated lymphocyte cultures from patients with ATP had enhanced IgG production compared with normal individuals. Since these initial observations were reported, abnormal cell-mediated immunity (CMI) against platelets in patients with ATP has been reported by several laboratories. Autologous platelets, o r their membranes, have been shown to stimulate lymphocytes from patients with ATP to produce increased quantities of a cytokine termed macrophage inhibition factor (MIF) when compared with control^'^.^' MIF was one of the first antigen stimulated-T cell derived cytokines described and was thought to play a role in maintaining macrophage numbers at sites of inflammation". It has a mw, of 23 kD, properties similar to interferon-y, and is now included in a group of cytokines termed macrophage activation factors (MAF)73-7B.Its enhanced production by T cells may reflect impaired immunore-

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Figure 2 Interleukin-2 production by platelet reactive (n=21, 0) and non reactive (n=12, V) lymphocytes from patients with ATP and normal controls (n=22, 0).supernatants were harvested on day 6 from a 7-day APC culture and tested for their ability to stimulate the proliferation of the IL-2 dependent cell line CTLL. Results are expressed as '[HI-thymidine incorporation (cpm). (Reproduced from Ref. 44 with permission.)

IMMUNORECULATION IN ATP

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Table 1 Summary of the lymphocyte defects in ATP. Parameter

Response Reference compared to normals

Leukocyte blastogenesis to platelets ConA stimulated IgG production T cell mediated Ig production MIF production IL-2 production Autologous mixed lymphocyte reaction CD8' T suppressor cell activity CD57' NK activity CDS' B cells/CD19' B cells CD8' T cells CD4' T cells CD4/CD8 ratio

Increased Increased Increased Increased Increased Decreased Decreased Decreased Increased Increased Increased Normal Decreased Increased Increased Decreased Decreased Increased

DR' T cells CD4'0T145' TcR phenotype CD4'2H2' Tsi cells CD4'Leu8' Tsi cells CD4TD8' T cells

44.68 70 44,46,83 7 0 . 7 1.79 44 80 46,80,83 84.85 40,44 44.48-54 53.54 52,53 50, 51 44,55 67 61 44 54

gulation in ATP. Borkowski et al.79 have further demonstrated that a dialysable lymphocyte extract derived from patients with ATP in remission could reduce in vitro MIF production to normal levels. These studies have raised the possibility that altered T cell-derived cytokine concentrations have a role in the pathogenesis of ATP, possibly by recruiting APC, such as macrophages, to the site of the immune response. Patients with ATP have lymphocytes which are defective in responding in autologous mixed lymphocyte cultures (AMLR)". The AMLR is an in vitro test of human T cell proliferative response to class I1 antigens and generates both CD4' helper and CD8' suppressor T cells. It was found that the patients with ATP, who were low responders in the AMLR, had a serum IgG antibody which suppressed the reactivity. Figure 2 shows results from our laboratory that indicate that when normal platelets are added to 7 day AMLRs (APC assays), CD4' T helper cells proliferate and secrete significantly higher amounts of interleukin-2 (IL-2) than do lymphocytes from control subj e c d 8 . IL-2 plays a central role in regulating human B cell activation, proliferation and differentiation, thereby enhancing the production of immunoglobulins". It may be that the inhibitory IgG in the serum of patients with ATPso retards CD8' T suppressor cell activity, allowing CD4' T helper cells to respond abnormally. Such imbalances of suppress0r:helper cells have been seen in patients with SLER2.With respect to this possibility, Hymes er a/.*' recently demonstrated a decreased CD8' T suppressor cell function in patients with ATP; this dysfunction was associated with (a) enhanced in vitro immunoglobulin production by the patient's EBV-transformed B lymphocytes and (b) a complement-fixing IgG antibody in

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the patient's serum, which was specific for the CD8' T suppressor cellsS3.It was speculated that the complement-fixing IgG antibody may ultimately alter the balance between suppression and help, and enhance autoantibody productions3. These observations lend support to the hypothesis that anti-platelet autoantibody production in ATP is primarily the result of abnormal T cell immunoregulation. Table 1 summarizes the T lymphocyte defects in ATP and although many of these defects may be related, further studies are required to determine the detailed mechanism( s) of how T cells are stimulated by autoantigen(s) (i.e. platelets) to regulate the autoantibody response in ATP. NATURAL KILLER (NK) CELLS NK activity has been shown to be generally suppressed in autoimmune diseases including ATP. Suppressed NK activity against K562 targets has recently been described in patients with chronic ATP, despite the patients having normal numbers of circulating NK ~ e l l s * ~ Patients ~ ~ * . with ATP had an average NK activity of 18f19 LU2,,% as compared with 65+ 25 LU20%in normal controlss4. The reasons for this suppression are unclear, but since NK cells are known to inhibit the proliferation and production of antibodies by B lymphocyte^^^*^^, it is possible that the NK cell defect may influence anti-platelet autoantibody production. CYTOKINES IN ATP The important role played by cytokines in human autoimmune states is becoming increasingly evident, and a number of reviews have been published on this s ~ b j e c t ~ It* ~is~likely ~. that a careful analysis of the interaction of various cytokines with B lymphocytes from patients with ATP would assist understanding of the mechanisms of anti-platelet autoantibody production. Many of the cytokine defects in chronic ATP have been mentioned earlier. This section will primarily discuss recent developments in cytokine therapy in chronic ATP. Clinically, interferon a-2b has been used by several investigators in the management of patients with chronic [email protected] et a1.90in particular, have shown increased platelet increments in patients with chronic ATP treated with interferon a-2b. Other investigators, however, have shown only transient increases in platelet counts with interferon a-2b9i'92. The mechanism of action of this therapy is unknown, but interferon a-2b does have a variety of related in vitro and in vivo effects, including activation of NK cells93,IL-2 antagonism and high-dose suppression of

J. W. SEMPLE AND J. FREEDMAN

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Figure 3 Summary of the possible interrelationships between lymphocyte subsets in patients with ATP. Hatched lines represent decreased activity and reduced signals (arrows) whereas thick solid lines represent enhanced activity and positive signals (arrows). Thin solid lines represent presumably normal activity (i.e. platelets and macrophages)

humoral immune responsesy4. The possibility exists that this form of therapy may correct the suppressed NK activity and enhanced IL-2 activity seen in patients with ATP4".R4;this, in turn, could ultimately reduce the autoantibody response. More studies are clearly required to address these possible mechanisms. When enriched B lymphocytes from patients with ATP are exposed to IL-2 in v i m , anti-platelet antibody production is enhanced4'. In contrast however, 7interferon alone has no effect on B cells, but can synergise with IL-2 to stimulate antibody production4'. It is clear that further study is required to determine what exact roles these cytokines play in the anti-platelet autoantibody response and whether they may be of beneficial use in the treatment of chronic ATP.

CONCLUSIONS AND FUTURE CONSIDERATlONS To date, the studies of cellular immunity in chronic ATP indicate that multiple lymphocyte defects exist, however, some conflicting reports suggest that further

study is required in order to elucidate the exact pathophysiological mechanisms of this autoimmune disease. Some of the reported defects, however, appear to be interrelated and their cumulative effects may be, in part, responsible for anti-platelet autoantibody production. For example, CDS' T suppressor cells hypo-responsiveness8', with concomitant increased autoreactive T helper cells44,may be responsible for regulating autoantibody production, but it is not known whether one or both are pimarily responsible. Figure 3 presents a model, based on several reports from the literature, of how cellular immunity might be involved in the induction of anti-platelet autoantibody production in patients with ATP. Since enhanced anti-platelet T helper cell activity can induce autoantibodies in vitro, studies on this particular mechanism may enhance understanding of the model. We are studying the influence of CD4' T helper cell derived cytokines on anti-platelet autoantibody production and attempting to identify the autoantigen(s) associated with platelets which stimuIate these T helper cells. Such studies will allow better understanding of the mechanisms of autoantibody production in patients with chronic ATP and may lead to development of immuno-specific therapeutic approaches for the management of ATP.

IMMUNOREGULATION IN ATP

Acknowledgements We thank Dr F. Nestel (Dept. of Physiology, McGill University, Montreal, Que.) for his helpful discussions. This work was supported by grants from the St Michael’s Hospital Research Society and the Medical Research Council of Canada (MT-I 1676).

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Cellular immune mechanisms in chronic autoimmune thrombocytopenic purpura (ATP).

Chronic autoimmune thrombocytopenic purpura (ATP) is a common autoimmune-mediated bleeding disease in which autoantibodies are directed against platel...
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