1. RHEUMATIC FEVER 2. CHAGAS DISEASE 3. Myocarditis

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2 Although the vast majority of cardiac diseases relate to the presence of atherosclerosis in the vessels supplying blood and oxygen to the heart, there are certain conditions in which immunological events play an important role. 1. RHEUMATIC FEVER 2. CHAGAS DISEASE 3. Myocarditis

3 Rheumatic fever Rheumatic fever is an inflammatory disease that occurs following a A streptococcus infection. Is a delayed, nonsuppurative sequela of a pharyngeal infection with the group A streptococcus

4 Epidemiology Ages 5-15 yrs are most susceptible Rare <3 yrs Girls>boys Common in 3rd world countries Incidence more during fall,winter & early spring

5 Manifestations A latent period of two to three weeks follows the initial streptococcal pharyngitis. The onset of disease is usually characterized by an acute febrile illness, which may manifest itself in one of three classical ways: (1)The patient may present with migratory arthritis predominantly involving the large joints of the body. (2) Carditis and valvulitis, or carditis and valvulitis may be the only signs of an acute episode. (3) There may be involvement of the central nervous system, manifesting itself as Sydenham s chorea.

6 MOLECULAR MIMICRY IN RHEUMATIC FEVER Many of the antigens present in the group A streptococcus cross-react with antigens present in mammalian tissues. Thus, antibodies present in the sera of ARF patients bind to cardiac tissue or cells in the caudate nucleus or to human kidney tissues.

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9 Pathogenesis Although there is little evidence for the direct involvement of group A streptococci in the affected tissues of ARF patients, a large body of epidemiological and immunological evidence indirectly implicates the group A streptococcus in the initiation of the disease process: (1) It is well known that outbreaks of ARF closely follow epidemics of either streptococcal sore throats or scarlet fever. (2) Adequate treatment of a documented streptococcal pharyngitis markedly reduces the incidence of subsequent ARF. (3) Appropriate antimicrobial prophylaxis prevents the recurrences of disease in known patients with acute ARF.

10 Etiologic Considerations At least three main theories have been proposed: The first theory : Is concerned with the question of whether persistence of the organism is important. No investigators have been able to consistently and reproducibly demonstrate live organisms in rheumatic fever joints, cardiac tissues, or valves.

11 The second theory: Is concerned with deposition of toxic products is required certain streptococcal pyrogenic exotoxins (A and C) may act as superantigens. These antigens may stimulate large numbers of T cells through their unique bridging interaction with T-cell receptors and class II MHC molecules. Once activated, these cells elaborate tumor necrosis factor, gamma interferon, and a number of interleukin moieties, thereby contributing to the initiation of pathological damage

12 The third theory: Perhaps the best evidence to date favors the theory of an abnormal host immune response (both humoral and cellular) in the genetically susceptible individual to those streptococcal antigens cross-reactive with mammalian tissues. The evidence supporting this theory can be divided into three broad categories: 1.The presence of heart-reactive antibodies in ARF sera. 2. Sera from patients with ARF also contain increased levels of antibodies to both myosin and tropomyosin, and keratin as compared with sera from patients with pharyngeal streptococcal infections that do not develop ARF. These myosin-affinity purified antibodies also cross-react with M protein moieties (known to share amino acid homology with myosin), suggesting this molecule could be the antigenic stimulus for the production of myosin antibodies in these sera.

13 3.Finally, as indicated earlier, autoimmune antibodies are a prominent finding in another major clinical manifestation of ARF, namely, Sydenham s chorea, and these antibodies are directed against the cells of the caudate nucleus. A number of chorea patients presented with behavioral disorders such as tics or obsessive-compulsive disorders (OCD). Streptococci and probably other microbes may induce antibodies, which functionally disrupt the basal ganglia pathways leading not only to classical chorea but also to other behavioral disorders in these children without evidence of classical chorea.

14 4. In all cases in which autoreactive antibodies are seen (heart, brain, cardiac valves, kidney), they can be absorbed with streptococcal antigens, notably those streptococcal antigens of the M protein that share homology with human myosin, tropomyosin, keratin, and so on.

15 At a cellular level : There is now ample evidence for the presence of both lymphocytes and macrophages at the site of pathological damage in the heart valves in patients with ARF. The cells are predominantly CD4+ helper lymphocytes during acute stages of the disease. The ratio of CD4+/CD8+ lymphocytes (2:1) more closely approximatesthe normal ratio in chronic valvular specimens. This abnormal reactivity peaks at six months after the attack but may persist for as long as two years after the initial episode. Once again, the reactivity was specific only for those strains associated with ARF.

16 o all rheumatic fever patients express abnormal levels of D8/17- positive B cells, especially during the acute attack. o Monoclonal antibody D8/17 identifies a B lymphocyte antigen with expanded expression in nearly all patients with rheumatic fever and is thought to be a trait marker for susceptibility to this complication of group A streptococcal infection. o In those cases where the diagnosis of ARF has been doubtful, a strong association of the D8/17 B-cell marker with children with OCD. o presence of elevated levels of D8/17-positive B cells has proven to be helpful in establishing the correct diagnosis.

17 بسم هللا الرمحن الرحمي Reham abu Husin

18 Etiology Acute rheumatic fever is a systemic disease of childhood,often recurrent that follows group A beta hemolytic streptococcal infection It is a delayed non-suppurative sequelae to URTI with GABH streptococci. It is a diffuse inflammatory disease of connective tissue,primarily involving heart,blood vessels,joints, subcut.tissue and CNS

19 Genetics That ARF might be the result of a host genetic predisposition has intrigued investigators for over a century. It has been variously suggested that the disease gene is transmitted: in an autosomal dominant fashion, in an autosomal recessive fashion with limited penetrance, or that it is possibly related to the genes conferring blood group secretor status.

20 Renewed interest in the genetics of ARF occurred with the recognition that gene products of the human MHC (major histocompatibility complex) were associated with certain clinical disease states.

21 Using an alloserum from a multiparous donor, an increased frequency of a B-cell alloantigen was reported in several genetically distinctand ethnically diverse populations of ARF individuals and was not MHC related.

22 Most recently, a monoclonal antibody(d8/17) was prepared by immunizing mice with B cells from an ARF patient. A B-cell antigen identified by this antibody was found to be expressed on increased numbers of B cells in 100 percent of rheumatic fever patients of diverse ethnic origins and only in 10 percent of normal individuals. The antigen defined by this monoclonal antibody showed no association with or linkage to any of the known MHC haplotypes, nor did it appear to be related to B-cell activation antigens.

23 These studies are in contrast to other reports in which an increased frequency of certain human leucocytes antigens (HLAs) was seen in ARF patients. There are marked differences in the increased frequency of the HLAs, depending on the racial features of the patient group. These seemingly conflicting results concerning HLA and RF susceptibility prompt speculation that these reported associations might be of class II genes close to (or in linkage disequilibrium with) but not identical to the putatative RF susceptibility gene.

24 Alternatively, and more likely, susceptibility to ARF is polygenic, and the D8/17 antigen might be associated with only one of the genes (i.e., those of the MHC encoding for the D-related [DR] antigens) conferring susceptibility. Although the full explanation remains to be determined, the presence of the D8/17 antigen does appear to identify a population at special risk of contracting ARF.

25 Streptococcal Vaccine Candidates As early as the 1930s, researchers were pursuing the study of streptococcal vaccinations, with the injection of whole killed group A streptococci and cell walls, thereof culminating in injections of partially purified M protein extracts in the1970s. However, all interest, especially by the pharmaceutical companies, ceased at that point because the U.S. Food and Drug Administration (FDA) proclaimed that one could work on streptococcal vaccines as long as no streptococcal component was used!.

26 The FDA was afraid that induction of antibodies cross-reactive with human tissues, especially cardiac tissues,could be detrimental to the vaccine. However, it was soon apparent that many individuals had antibodies cross-reactive with a variety of human tissues and were perfectly normal.

27 In the past decade, the restriction was removed on the condition that toxicity studies in animals did not reveal any deletion effects in the animals when injected with a streptococcal vaccine candidate. This ushered in the search for an effective,safe, and inexpensive group A streptococcal vaccine, and there are now at least four prominent candidates with more in the pipeline:

28 1. Perhaps the most advanced candidate is by Dale and colleagues (1996), which is synthetic peptide sequences of a variety of M protein types taken from the variable region of the M protein and hooked together by linkers. This has induced protective immunity in animals to a number of different M protein types and is safe for use in humans. Clinical trial of its efficacy to prevent streptococcal infections is currently under way.

29 2. The use of the C-repeat constant region of the M protein advanced by Fischetti (1989) produces protection against oral colonization of the throat by group A streptococci.

30 3. A surface protein called C5 peptidase, which is present on the surface of all group A and group B streptococci, produces antibodies that block both the colonization of group A and group B streptococci in oral colonization studies.

31 4. The streptococcal group A carbohydrate (CHO) as proposed by Zabriskie and colleagues has been purifi ed and used as an immunogen to protect against streptococcal infections. This vaccine candidate promotes phagocytosis of group A streptococci of several different M types, will protect against infection using passive and active immunization studies, and also protects against oral colonization.

32 The confirmed observation of an increased frequency of a B-cell alloantigen in several populations of rheumatics suggests that it might be possible to identify individual ssusceptible to ARF at birth. If so, then from a public health standpoint, these individuals would be prime candidates for immunization with any streptococcal vaccine that might be developed in the future.

33 Directions for Future Research Do super antigens play a role in this transformation? Are particular cytokines and lymphokines present during the quiescent period? Are cellular mechanisms at work, and if so,what cells are involved? These questions are important because the answers to those questions in ARF may hold keys to unlocking other rheumatic diseases!!!

34 Finally, one of the most intriguing, unresolved questions has been: the possible association of the group A streptococcus with behavioral disorders such as OCD (Obsessive compulsive disorder ), tics, Tourette s syndrome, and anorexia nervosa????!!!

35 Even as early as the 1890s, Osler observed in his textbook of medicine that many of his former Sydenham s chorea patients (a well-known neurological manifestation of a streptococcal infection) often were later seen as patients in the behavioral disorder clinics. One can also expand these concepts to other organisms in which there may be shared antigenicity between microbial and mammalian antigens.

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37 Brazilian physician Carlos Chagas who first discovered the parasite responsible for the signs and symptoms of the disease.

38 Also called American trypanosomiasis Caused by a protozoan Trypanosoma cruzi infects humans and animals through an insect called a kissing bug /reduviid bug.. The disease can be seen in dogs and humans and initially causes flulike signs (fever, headache), which can progress to heart failure over along period of time. Systemic protozoal disease

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40 20 million infected 100 million at risk higher in South America

41 Accidental oral ingestion of reduviid bugs, which release metacyclic trypomastigotes to invade the oral mucosal cells Vertically from mother to child( months 5-9 of pregnancy) CONGENITAL TRANSMISSION 10% Blood transfusions 12-25%

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44 Innate immune response Tissue tropism Animal models

45 Early in infection host depend on innate immune ( macrophages and (NK) Unactivated macrophages little ability to kill T. cruzi for parasite replication Within two hours of macrophage invasion, the majority of T. cruzi have escaped the phagosome and exist free in the host cytoplasm avoiding degradation by intracellular microbicidal enzymes A variety of stimuli for priming macrophages IFN-γ (IL-2, IL-3, IL-4, and IL-5) IFN-γ + purified IL-4 no better-anti-il-4 antibodies Lipopolysaccharide significantly increases the trypanocidal effect of IFN-γ on macrophages granulocyte-macrophage colony-stimulating factor

46 NK cells participate in the innate immune response secrete IFN-γ after incubation with T. cruzi in vitro Since IFN-γ activates macrophages to kill T. cruzi, the role of NK cells in T. cruzi infection would be expected to be protective IFN-γ that helps control parasite replication before the acquired immune response becomes predominant may also be involved in the immune response later in infection

47 Serum taken from an uninfected human does not lyse trypomastigotes, but serum infected patients does the complement system requires acquired immune response to T. cruzi to become operational Parasite lysis primarily via the alternative complement pathway direct association of (C3) with the parasite surface, rather than by fixation of complement by antibody Fc receptors effect of immune antibodies on complement lysis of trypomastigotes was a function of the specificity of the antigenbinding sites there was a surface component on the parasites when neutralized by immune sera the parasites susceptible to complement lysis

48 gp160 specific parasite product bound the complement component C3b and inhibited C3 convertase formation, thus inhibiting activation of the alternative complement pathway is membrane bound and shares genetic and functional similarities to the human complement regulatory protein, decay accelerating factor restrict classic complement activation The T. cruzi complement regulatory protein is stage specific in that it is only expressed by mammalian forms of the parasite

49 Growth in muscle and nervous tissue is more likely to be related to a strategy for long-term parasite survival in the host, rather than a strategy related to direct transmission to secondary hosts. IFN-γ induction of macrophage trypanocidal activity is associated with the production of hydrogen peroxide * However, treatment of activated macrophages with catalase, superoxide dismutase, or sodium benzoate to scavenge respiratory burst metabolites failed to inhibit trypanocidal activity in vitro, suggesting an oxygen-independent mechanism of T. cruzi destruction

50 Macrophages primed with IFN-γ produce NO NO may be directly toxic to T. cruzi; however, it reacts with superoxide(o2 ) to yield peroxynitrite (ONDO ), which is highly toxic In vivo, inducible nitric oxide synthase (inos) is induced at the protein and messenger RNA levels, and NO is released during acute infection The IFN- γ induced, NO-dependent mechanism of macrophage killing of T. cruzi can be inhibited by the addition of interleukin-10 or transforming growth factor-β in vitro

51 In mice, parasites apparent in blood 5-7 d after infection and rise until 3or 4 w. RAG knockout mice( deficient in both B- and T-cell function) have similar levels of parasitemia compared with wild-type mice until day 13 of infection, parasitemia level becomes higher in the RAG knockouts. This indicates that the acquired immune response has little effect until about 2w. Although anti T. cruzi antibodies are detectable at about day 7 in murine models, protective antibodies are not present until several weeks later Both IgG subclasses 1 and 2 are capable of clearing T. cruzi Antibodies mediate protection from T. cruzi by opsonization, complement activation, and antibody-dependent cellular cytotoxicity

52 Experiments in mice showed that T-cell activation correlated with resistance to infection Deficient T-cell function is associated with increased sensitivity to infection Mice that are depleted of T cells (CD4+ or CD8+) after they have survived the acute infection do not have altered parasitemia or longevity declining role of T cells and the importance of humoral immunity in controlling infection after the acute stage

53 T cells perform a variety of antiparasitic functions: provide helper T-cell function by stimulating B cells to produce parasite-specific antibody T-cell line derived from the spleens of T. cruzi infected mice was able to induce normal spleen cells to produce parasitic-directed antibodies when stimulated in vitro with T. cruzi antigen T cells produce cytokines in T. cruzi infection, which mediate important antiparasitic functions CD8+ T cells lyse T. cruzi infected host cells, which presumably interrupts the parasite life cycle, thus limiting its replication mice genetically deficient for genes controlling perforin or granzyme B mediated cytolytic pathways had parasitemia and mortality rates similar to wild-type mice, suggesting that cytolytic function, in fact, may not be the protective effector mechanism of CD8+ T cells T. cruzi specifi c CD8+ T cells produce IFN-γ and TNF-α upon stimulation, thus raising the possibility that these cells mediate their effects by cytokine release.

54 The inflammatory infiltrates consisted mainly of lymphocytes (60 90 percent) macrophages (10 40 percent). The lymphocytes primarily carried the T-cell marker, Thy1.2 Thy1.2+ cells were the major lymphocyte population in tissues (cardiac and skeletal muscle) during acute infection. Both CD4+ and CD8+ T cells were present in the infiltrates of skeletal muscle, sciatic nerve, and spinal cord. a slight predominance of CD8+ cells over CD4+, during the early chronic and late chronic stages CD8+ T cells (47 59 percent) dominated over CD4+ T cells (9 19 percent). B cells and macrophages each represented less than 1 percent

55 On standard histopathological study inflammatory lesions are found to co-localize with abundant parasites, demonstrating that inflammatory damage is directed to the parasite. Pathophysiology Disease results from an autoimmune response directed at the affected organ systems or from damage resulting from inflammation related to the persistence of the parasite autoimmune hypothesis observations that live T. cruzi parasites have been difficult to demonstrate in involved organs by conventional histological study autoimmune T cells and antibodies develop during infection with T. cruzi Some T. cruzi antigens molecularly mimic affected host tissues chronic infection leads to loss of tolerance and, combined with antigenic mimicry, results in specific autoimmune attack of cardiac, gut, and peripheral nervous tissues.

56 Other hypothesis progressive inflammation directed at parasites that reside in target organs cause the pathologic damage of chronic infection Studies that support this hypothesis have found that parasite antigens and DNA can be detected in many chronic inflammatory infiltrate and that parasitologic treatment of chronically infected animals or humans tends to lead to improvement and resolution of disease

57 The theory of autoimmunity supported by a number of observations 1- Few parasites can be demonstrated in the inflammatory lesions by conventional histological study. -This observation suggests the disease may not be driven solely by reaction to the parasite 2- Only 10 to 30 %of chronically infected people develop Chagas disease, although most can be shown to have chronic parasitemia. - This suggests that, in addition to chronic T. cruzi infection, some other factor(s) develops disease. -Susceptibility to autoimmune disease 3- Chronic Chagas disease is very organ specific, generally limited to the heart, nervous tissues, or innervation of the gut. - suggests that additional specificity of Chagas disease is imposed during infection, perhaps by the particular autoimmune response that is generated by chronic T. cruzi infecion. 4- The long lag time from infection to disease could be necessary to generate disease by autoimmunity. 5- The presence of autoimmune T cells and antibodies in infected individuals, especially when they are associated with disease, is evidence that autoimmunity may play a role in pathogenesis.

58 Autoimmune antibodies are easily demonstrated in T. cruzi-infected individuals. Antibodies to myocardium and nervous tissues are found in high levels myocardium and nervous tissues are key organs that are damaged in chronic Chagas disease, finding antibodies to these tissues could mean that these antibodies cause autoimmune damage to these tissues antigens from myocardium and nervous tissues are probably exposed by the damage of infection of these organs, and antibodies may be generated to these tissues without being pathogenic Many of the autoantibodies found in the sera of T. cruzi infected persons and mice are so-called natural autoantibodies The high levels of natural autoantibodies after T. cruzi infection may be the result of the polyclonal lymphocytic proliferative response that occurs during acute infection Levels of natural autoantibodies do not correlate with diseases in individuals who are chronically infected with T. cruzi.

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62 Alternative theory parasites residing in chronically infected host tissue may cause chronic disease by either damaging tissues directly or focusing the inflammatory response in host tissues properties autoimmune hypothesis may also be possible with parasite-directed pathogenesis Parasites may be difficult to demonstrate in the lesions due to limitations of present techniques not all chronically infected individuals develop chronic disease reflect parasite burden, strain differences, or host variation in the immune response organ specificity due to tropism of the parasite for cardiac and neuronal tissues long lag time to develop disease due to the slowly progressive damage Two other factors support the parasite- directed damage o o First, immunosuppression exacerbates the disease process and causes worsening of the pathologic lesions of Chagas disease second factor is that treatment with antiparasitic drugs in early Chagas disease markedly lessened the progression to chronic disease, although the number of patients assigned to treatment versus placebo groups was small.

63 بسم اهلل الرحمن الرحيم

64 Myocarditis Myocarditis is an inflammation of the myocardium

65 Major features: Arrhythmia,CHF,cardiogenic shock. In ECG: Non-specific ST wave changes. Echocardiogram: Normal ventricular size but decrease contractility. chronic cases: heart enlargement with thinning of the muscle. both ventricles may be affected.

66 Diagnosis None of the clinical features described are diagnostic for myocarditis and until the use of the endomyocardial biotome, the diagnosis could only be established with certainty by postmortem examination.

67 Incidence The incidence of the disease varies from 1 to 10/100,000. Many patients recover spontaneously inter supportive treatment. five-year survival of giant cell myocarditis is only 56 %. in pediatric patients, the mortality rates may be even higher.

68 Dilated Cardiomyopathy DCM is a chronic form of heart disease. Characterized by right ventricular dilation and impaired contraction.

69 Signs and symptoms Asymptomatic cardiomopathy. severe congestive heart Failure. Arrhythmias. Systemic pulmonary vein congestion. mitral or tricuspid regurgitation.

70 Incidence incidence10/100,000. Poor outcome. five-year mortality of 46 %.

71 Etiologic Considerations of both Myocarditis and DCM In both myocarditis and DCM, there appears to be an association with prior Coxsackie virus infections. In children and infants with DCM, significantly increased titers of neutralizing antibody to the virus has been found. Coxsackie virus,b specific nucleic acid sequences have been found in the heart tissues of a small number of these patients.

72 Autoimmune Considerations There is role of autoantibodies to the heart. antibody localized on the myocyte, giving a sarcolemmal, myolemnal pattern or on the striations, producing a fibrillar pattern. myocarditis sera reacted more to myosin heavy chain. cardiomyopathy sera reacted more to muscle actin.

73 ELISA studies have revealed that autoantibodies to ANT were elevated in 24/32 patients with DCM. So many patients with myocarditis and with DCM develop autoantibodies to a number of cardiac constituents. ANT: Adenosine Nucleotide Translocator.

74 None of these antibodies to cardiac antigens is known to play a direct pathogenetic role in the disease. However, the presence of antibodies to β1- adrenergic receptors in DCM and Chagas disease is highly suggestive of a direct pathogenetic effect, since the antigen is accessible on the surface of the myocardiocyte.

75 β1-adrenergic receptor antibodies can induce apoptosis in isolated adult cardiomyocytes and antibodies activating the receptors are associated with reduced cardiac function in chronic heart failure. Antibodies to the mitochondrial antigens, ANT and BCKD, may also have adverse consequences on cardiac function. It is not clear, however, whether these antibodies have access to their target antigens in vivo. BCKD:mitochondrial branched-chain α-ketoacid dehydrogenase.

76 Genetic Features relationship with the human MHC (HLA). DCM patients had an increased frequency of HLA-DR4 and a decreased frequency of HLA-DR6. The largest study to date reconfirmed these findings and also found that DR4-Dqw4 haplotype conferred heightened risk of disease.

77 A predominance of myocarditis in males has been reported in a number of studies. The proportion of male patients is about 60 percent. In this respect, myocarditis differs from most autoimmune diseases,which predominantly affect females.

78 Environmental Features Myocarditis has both infectious and noninfectious causes. Acute myocarditis is associated with infections of many types,including bacterial, rickettsial, viral, mycotic, protozoan, and helminthic.

79 the most common agents are : enteroviruses and the adenoviruses. Coxsackie virus group B infections were associated with at least half of the acute cases of myocarditits Coxsackie virus B antigen was found in the myocardium of 30.9 % of routine autopsy specimens of myocarditis. Serotype B3 is identified most frequently.

80 Treatment and Outcome supportive therapies bed rest. treatment of heart failure, arrhythmias, and embolic events if present. Cardiac transplantation in patients with refractory heart failure.

81 immunosuppressive therapy Some individuals respond well to immunosuppression (prednisone and cyclosporine), others fail to respond or even have serious adverse reactions that preclude continued treatment.

82 The major problem at present is the difficulty in distinguishing immunemediated cardiac disease from infectious, genetic, or toxic forms of the disease. So treatment cannot be rational or capable of evaluation.

83 Future Directions for Research The future treatment of autoimmune disease in general depends on early prediction and appropriate prevention.

84 The initial goal is : to identify patients with viral myocarditis who are likely to progress to an autoimmune disorder. Susceptible strains of mice produce somewhat higher levels of certain key cytokines such as IL-1β and TNF-α. Early elevation in these or similar key cytokines may provide useful biomarkers for subsequent autoimmune disease.

85 evidence shows that inhibiting some critical cytokines at the earliest stages of pathogenesis can avoid the autoimmune sequelae of viral infection. For example, administration of either the IL-1β receptor antagonist or monoclonal antibodyto TNF-α prevents the development of autoimmune myocarditis.

86 The second goal is: to identify patients with autoimmune myocarditis who are most likely to progress to irreversible DCM. Early data suggest that two key cytokines, IFN-γ and IL- 13, exert important protective effects during autoimmune myocarditis. Consequently, mice deficient in either of these cytokine markers are likely to progress to a severe form of dilatedcardiopathy.

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