Aschoff bodies of rheumatic carditis are granulomatous lesions of histiocytic origin

The histogenesis of the Aschoff body of rheumatic carditis is controversial. Proliferative Aschoff bodies in heart sections from 6 patients with acute rheumatic heart disease were tested by avidin-biotin peroxidase labeling methods for the presence of desmin, muscle-specific actin, S-100, neurofilament, leukocyte common antigen, receptor for Ulex europeus I lectin, Factor VIII-related antigen, vimentin, alpha 1-antichymotrypsin, and myeloid/histiocyte antigen. Lack of Aschoff body labeling for desmin and muscle-specific actin, S-100 and neurofilament, and Ulex europeus I and Factor VIII-related antigen is not consistent with histogenesis from smooth or striated cardiac muscle, nerve or nerve sheath, and lymphatic or vascular endothelium, respectively. Strong labeling of Aschoff body cells for vimentin is evidence for a mesenchymal origin, and labeling for myeloid/histiocyte antigen is consistent with a histiocytic origin. Furthermore, weak, variable labeling of Aschoff body cells for leukocyte common antigen suggests that at least some Aschoff body cells were originally derived from blood-borne monocytes. Both multinucleated Aschoff cells and "owl's eye," Anitschkow cells label identically, suggesting a common origin. Alpha 1-Antichymotrypsin, a widely utilized marker of histiocytes, was unexpectedly negative. Perhaps histiocytes that form Aschoff bodies do not express this lysosomal enzyme. Aschoff bodies appear to be a unique and distinctive form of granuloma.     

Induction of autoimmune valvular heart disease by recombinant streptococcal m protein

Rheumatic heart disease is an autoimmune sequela of group A streptococcal infection. Previous studies have established that streptococcal M protein is structurally and immunologically similar to cardiac myosin, a well-known mediator of inflammatory heart disease. In this study, we investigated the hypothesis that streptococcal M protein could produce inflammatory valvular heart lesions similar to those seen in rheumatic fever (RF). Fifty percent (3 of 6) of Lewis rats immunized with recombinant type 6 streptococcal M protein (rM6) developed valvulitis as well as focal lesions of myocarditis. Valvular lesions initiated at the valve surface endothelium spread into the valve. Anitschkow cells and verruca-like lesions were present. T cells from rM6-immunized rats proliferated in the presence of purified cardiac myosin, but not skeletal myosin. A T-cell line produced from rM6-treated rats proliferated in the presence of cardiac myosin and rM6 protein. The study demonstrates that the Lewis rat is a model of valvular heart disease and that streptococcal M protein can induce an autoimmune cell-mediated immune attack on the heart valve in an animal model. The data support the hypothesis that a bacterial antigen can break immune tolerance in vivo, an important concept in autoimmunity.     

Immunoreactivity of anti-streptococcal monoclonal antibodies to human heart valves. Evidence for multiple cross-reactive epitopes.

Association of group A streptococci with acute rheumatic fever and valvular heart disease is well established; however the basis of valve injury remains unclear. In this study, anti-streptococcal monoclonal antibodies (MAbs) cross-reactive with myocardium were reacted with sections from 22 rheumatic valves, nine normal, five endocarditic, one 'floppy,' and one Marfan valve. In immunohistochemical studies, MAb reactivity was observed with cardiac myocytes, smooth muscle cells, cell surface and cytoplasm of endothelial cells lining valves, and valvular interstitial cells. Endothelial basement membrane and elastin fibrils reacted with the MAbs, whereas collagen was unreactive. Similar reactivity was seen with sera from acute rheumatic fever patients. The anti-streptococcal MAbs reacted with intravalvular myosin and vimentin in Western blots, and purified elastin competitively inhibited the binding of the anti-streptococcal MAbs to whole group A streptococci. The data show that human heart valves have numerous sites of immunoreactivity with anti-streptococcal MAbs and acute rheumatic fever sera of potential importance in the pathogenesis of rheumatic valvular injury.     

Rheumatic heart disease in a patient with acquired immunodeficiency syndrome

Acute rheumatic heart disease (RHD) with Aschoff nodules and biventricular dilation was diagnosed at autopsy in a patient with acquired immunodeficiency syndrome who died of pneumonia due to Pneumocystis carinii. The relationship of acute RHD and human immunodeficiency virus-associated immune deficiency is discussed.     

Thrombotic endocarditis and lupus anticoagulant. A pathogenetic possibility for idiopathic 'rheumatic type' valvular heart disease

Lupus anticoagulant and anti-phospholipid antibodies are well recognized as being associated with thromboembolic disorders in patients both with and without systemic lupus erythematosus (SLE). There have been recent reports of the association of lupus anticoagulant and antiphospholipid antibodies with severe valvular heart disease in patients with SLE and it has been suggested that organizing thrombus on the surface of the valve may be a cause of distortion and subsequent dysfunction. We describe two patients who did not have SLE, but who did have both lupus anticoagulant and antiphospholipid antibodies. Both had severe valvular heart disease, the pathology of which demonstrates valve distortion by layers of organizing thrombus identical to that of previously described patients with SLE. The gross appearance of these valves is similar to that of the valves in "rheumatic" heart disease. We suggest that in some patients with "rheumatic" heart disease, but without a history of rheumatic fever, the prothrombotic tendency associated with lupus anticoagulant and phospholipid antibodies may either contribute to, or be responsible for, the pathogenesis of "rheumatic" type valve deformities.     

Cardiac pathologic findings in patients treated with bone marrow transplantation.

Cardiac pathologic findings were analyzed in 22 necropsy cases from a series of 29 patients with leukemia, aplastic anemia, or metastatic cancer who had been treated with ablative therapy followed by bone marrow transplantation. Some cardiac alterations were similar to those that occur in patients with hematologic and neoplastic diseases not treated with bone marrow transplantation, and consisted of cardiomegaly, cardiac atrophy, hemorrhage, foci of necrosis due to shock associated with sepsis or hepatic failure, myocardial abscesses secondary to systemic candidiasis or staphylococcal infection, fibrinous pericarditis, and hemosiderosis. Other cardiac alterations were more specifically related to factors associated with transplantation procedure. Six patients exhibited a distinctive interstitial reactive change characterized by the presence of (1) moderate to large numbers of Anitschkow cells, occurring alone or in small cellular aggregates and histiocytes, histiocytic cells with nuclei of the Anitschkow type, lymphoid cells, and plasma cells, and (2) nuclei of the Anitschkow type in cardiac vascular and endocardial smooth muscle, endothelial and Schwann cells, and occasional cardiac muscle cells. This alteration may have been induced by abnormal immune mechanisms, as suggested by the observation that five of the six patients with interstitial change had clinical evidence of graft-versus-host disease. Two patients developed fatal congestive cardiac failure in the early post-transplant period and exhibited myocardial damage with histologic and post-transplant period features indicative of severe acute injury. Findings in these two patients consisted of necrotic muscle cells, which exhibited multiple contraction bands, diastase-resistant PAS staining, and intracellular fibrin deposits; microthrombi, which were composed of fibrin and occasionally of fibrin and platelets; and extravasated erythrocytes and fibrin strands in the interstitium. One of the two patients also exhibited unusual nuclear alterations, which were characterized by replacement of normal chromatin by palely stained fibrous and filamentous material. Clinicopathologic analysis strongly suggested that the fatal cardiotoxicity in both patients resulted primarily from effects of high doses of cyclophosphamide, which were administered as part of a four drug regimen that provided tumor ablation and immunosuppression for bone marrow transplantation. Our findings emphasize the need for less toxic antineoplastic and immunosuppressive therapy for use in bone marrow transplantation procedures.     

Rheumatic fever and rheumatic heart disease: genetics and pathogenesis

Molecular mimicry between streptococcal and human proteins is considered as the triggering factor leading to autoimmunity in rheumatic fever (RF) and rheumatic heart disease (RHD). Here, we present a review of the genetic susceptibility markers involved in the development of RF/RHD and the major immunopathological events underlying the pathogenesis of RF and RHD. Several human leucocyte antigen (HLA) class II alleles are associated with the disease. Among these alleles, HLA-DR7 is predominantly observed in different ethnicities and is associated with the development of valvular lesions in RHD patients. Cardiac myosin is one of the major autoantigens involved in rheumatic heart lesions and several peptides from the LMM (light meromyosin) region were recognized by peripheral and intralesional T-cell clones from RF and RHD patients. The production of TNF-alpha and IFN-gamma from heart-infiltrating mononuclear cells suggests that Th-1 type cytokines are the mediators of RHD heart lesions while the presence of few interleukin-4 producing cells in the valve tissue contributes to the maintenance and progression of the valvular lesions.     

An Autopsy Case of Chronic Rheumatic Carditis with Myocardial Aschoff Bodies

An autopsy case of chronic rheumatic carditis is described. The patient was a woman aged 32 years and the duration of the disease was more than eight years.
At autopsy, the heart showed typical mitral stenosis with verrucous scarring, calcification and contraction of the valve. Areas of degenerating muscle cells and proliferation of the interstitial connective tissue, partly with perivascular infiltration, were seen throughout the myocardium, and heart muscles showed narrowing and fragmentation. There was fibrinoid degeneration of the wall in small coronary vessels. Numerous Aschoff bodies of various structures were found mostly in the proliferated interstitial connective tissue, between damaged muscle bundles and adjacent to the small coronary vessels of the myocardium. A small number of Aschoff bodies were situated in the subendocardial tissue in which there was no muscle.     

Rheumatic Fever,Autoimmunity, and Molecular Mimicry: The Streptococcal Connection

The group A streptococcus, Streptococcus pyogenes, and its link to autoimmune sequelae, has acquired a new level of understanding. Studies support the hypothesis that molecular mimicry between the group A streptococcus and heart or brain are important in directing immune responses in rheumatic fever. Rheumatic carditis, Sydenham chorea and a new group of behavioral disorders called pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections are reviewed with consideration of autoantibody and T cell responses and the role of molecular mimicry between the heart, brain and group A streptococcus as well as how immune responses contribute to pathogenic mechanisms in disease. In rheumatic carditis, studies have investigated human monoclonal autoantibodies and T cell clones for their crossreactivity and their mechanisms leading to valve damage in rheumatic heart disease. Although studies of human and animal sera from group A streptococcal diseases or immunization models have been crucial in providing clues to molecular mimicry and its role in the pathogenesis of rheumatic fever, study of human monoclonal autoantibodies have provided important insights into how antibodies against the valve may activate the valve endothelium and lead to T cell infiltration. Passive transfer of anti-streptococcal T cell lines in a rat model of rheumatic carditis illustrates effects of CD4+ T cells on the valve. Although Sydenham chorea has been known as the neurological manifestation of rheumatic fever for decades, the combination of autoimmunity and behavior is a relatively new concept linking brain, behavior and neuropsychiatric disorders with streptococcal infections. In Sydenham chorea, human mAbs and their expression in transgenic mice have linked autoimmunity to central dopamine pathways as well as dopamine receptors and dopaminergic neurons in basal ganglia. Taken together, the studies reviewed provide a basis for understanding streptococcal sequelae and how immune responses against group A streptococci influence autoimmunity and inflammatory responses in the heart and brain.     

Experimental coxsackievirus B4 valvulitis in squirrel monkeys

Mitral valve lesions were produced experimentally in three of nine squirrel monkeys inoculated intravenously or intraperitoneally with coxsackievirus B4 culture fluid. Aortic valve lesion also developed in one of these monkeys. Pathologic changes associated with acute, subacute, and chronic valvulitis noted in these monkeys are described. These studies demonstrate that coxsackievirus B4, a highly infectious agent to man, can produce valvular lesions in a nonhuman primate, the squirrel monkey. It is suggested that since coxsackieviral infection is common in man and since a substantial number of patients with chronic valvular heart disease present with no history of rheumatic fever and/or streptococcal infections, some instances of acute and chronic valvular disease in man generally attributed to rheumatic fever and the streptococcus are the result of viral infections instead of the streptococcus.     

Changes in atrial biopsies in chronic rheumatic heart disease. I: Cellulo-vascular and mesenchymal reaction

The cellular, vascular and connective tissue changes were studied in 32 atrial biopsy specimens from patients with chronic rheumatic heart disease (RHD). 15 of these 32 specimens showed some inflammatory reaction, 7 with small mononuclear cells only and 8 with macrophage reaction amidst increased but necrotic collagen, especially in the subepicardial and subendocardial regions. Most cellulonecrotic foci were histologically consistent with a stage of Aschoff nodule. Acid phosphatase activity in frozen sections was seen in the cytoplasm of the macrophages. Fine structural examination showed membrane-bound vacuoles and lipofuscin bodies rather than ingested material in the macrophages. By light and electronmicroscopy, these macrophages were not different from those encountered in other granulomatous or necrotic conditions. There was moderate proliferation of blood vessels, with prominence of endothelial cells and pinocytotic vesicles, or fibrosis of media, or proliferation of basal laminae. The presence of Aschoff nodules in the right atrium, the least affected chamber in RHD, suggests a diffuse and smouldering pathology on the basis of a persistent subclinical cell-mediated immune (CMI) reaction.     

Autoantibodies in the sera of patients with rheumatic heart disease: characterization of myocardial antigens by two-dimensional immunoblotting and N-terminal sequence analysis

The concept of antigenic mimicry in autoimmune diseases such as rheumatic fever has been under investigation for decades and the range of cross-reactive tissue antigens for streptococcal-induced antibodies identified in rheumatic heart disease is still expanding. To identify heart tissue-reactive antigens which may be implicated in the secondary immunopathogenesis of rheumatic fever, sera from 56 patients with acute rheumatic heart disease were probed in two-dimensional Western blots for reactivity against heart tissue antigens. After two-dimensional immunoblot analysis, proteins were submitted to N-terminal amino acid sequence analysis. This analysis identified creatine kinase, two mitochondrial proteins and, at a low level, various stress proteins as cross-reactive myocardial antigens. Therefore, in addition to myosin, creatine kinase may represent another major antigen for autoreactive antibodies in rheumatic heart disease. Mitochondrial proteins have been implicated in the pathogenesis of inflammatory heart disease for some years, and in this study we have identified two mitochondrial proteins as relevant antigens in rheumatic heart disease.     

Characterization of proximal colonic lymphoid tissue in the mouse

Here we describe a nodule of lymphoid tissue which was consistently located in the proximal colon of mice approximately 25% of the distance from the cecum to the rectum. Immunohistochemical characterization of this nodule demonstrated that the majority of lymphocytes were relatively immature 14.8+ (B220+), IgM+, Ia+ (specificity 20) B cells some of which were also Ly-1+. These nodules also possessed an occasional T cell (Thy-1+, Ly-1+, Lyt-2+) aggregate at the periphery. Rare, small areas did not stain for either T or B cell markers. These lymphoid nodules were associated with epithelial cells which stained positively with the ER-TR4 monoclonal antibody (which also recognizes thymic cortical epithelial cells) and also with ER-TR6, which has been reported to recognize thymic macrophages or dendritic cells. The overlying colonic epithelium stained intensely with the ER-TR4 monoclonal antibody. Proximal colonic lymphoid tissue was extremely sensitive to steroid treatment, losing approximately 80% of its mass within 24 hours in response to a single intraperitoneal injection of 2 mg hydrocortisone acetate. This response was similar to that of the thymus and to that reported for the bursa of Fabricius, but unlike that of other gastrointestinal lymphoid aggregates. These results indicated that proximal colonic lymphoid tissue contains a high frequency of relatively immature B cells and may be a primary site of their generation, possibly including some of the Ly-1+ phenotype. These observations correlate with new evidence suggesting that the allantois participates in the formation of the distal midgut, including its lymphoid components.     

Identification of mononuclear cells and T cell subsets in rheumatic valvulitis

The composition of the mononuclear cellular filtrates was investigated in 13 valve specimens from nine patients with rheumatic carditis, some of whom had clinical and laboratory evidence of acute disease at the time of surgery. In acute valvulitis (AV) as well as in chronic active valvulitis (CAV), the cellular infiltrates were primarily composed of T cells and macrophages. In AV the majority of these T cells were of the helper phenotype (Leu 3a). The T cells subsets were more heterogeneous in CAV. In five valves, the helper T cells exceeded the number of suppressor T cells, whereas in three others, helper and cytotoxic/suppressor T cells were present in equal numbers. The HLA-DR antigen was expressed by the majority of the mononuclear cells and by the vascular endothelium. These findings indicate that the valvular injury may at least in part be mediated by delayed-type hypersensitivity mechanisms. Those cells comprising the Aschoff body were primarily positive for the HLA-DR and a novel monoclonal antibody called D8/17 which identifies an antigen known to be present on the B cells of rheumatic fever patients.     

Leucocyte migration inhibition with human heart valve glycoproteins and group A streptococcal ribonucleic acid proteins in rheumatic heart disease and post-streptococcal glomerulonephritis.

Leucocyte migration inhibition (LMI) tests have been performed with leucocytes obtained from patients with acute rheumatic carditis, established rheumatic valvular disease with and without rheumatic reactivation, post-streptococcal glomerulonephritis and healthy volunteers, using human heart valve glycoprotein (HVGP) antigens and ribonucleic acid protein antigens (P-RNA) from Group A streptococci, types 5, 6 and 12 and a Group C streptococcus. Significantly increased LMI was observed with HVGP and P-RNA antigens of Group A streptococci in patients with clinical evidence of rheumatic valvular damage. Healthy volunteers and patients with poststreptococcal glomerulonephritis did not show any increase in LMI to these antigens. This suggests that cell-mediated immune mechanisms may be involved in the production of tissue lesions in rheumatic fever.     

Endometrial lymphoid tissue: an immunohistological study.

Lymphoid tissue of the endometrium was analysed by histological, immunohistological, and electron microscopical methods in 10 healthy uteri. A panel of monoclonal antibodies recognising macrophages (OKMI), HLA-DR antigen, B lymphocytes, T lymphocytes and their subsets, and dendritic reticulum cells was used in a two stage indirect immunoperoxidase labelling technique. Endometrial lymphoid tissue showed a remarkably consistent pattern of labelling in all cases. Lymphoid tissue was present in three sites: namely, (i) intraepithelial lymphocytes (predominantly T lymphocytes with occasional macrophages) associated with periglandular and sub-epithelial HLA-DR+, OKMI+ macrophages; (ii) interstitial lymphocytes and macrophages; (iii) lymphoid aggregates in the stratum basalis. These were composed mainly of T lymphocytes with a few B lymphocytes. Dendritic reticulum cells were found in those occasional lymphoid aggregates in which germinal centres were present. These features suggest that endometrial lymphoid tissue has many of the hallmarks of mucosal associated lymphoid tissue as found elsewhere in the body--for example, the bronchus and intestine. Endometrial lymphoid tissue appears to be unique, however, in that most of the stratum functionalis in which it is situated shows cyclical shedding during the menstrual cycle.     

Sex steroid receptors in lymphoid cells of human endometrium

Sex steroid hormone action on target tissues is mediated through binding of estrogen and progesterone to specific intranuclear proteins, the estrogen and progesterone receptors (ER and PR). Therefore, in the present report the authors investigated for the presence of ER and PR in lymphoid cells of endometrial stroma that may serve as potential targets for estrogen- and progesterone-mediated effects in endometrium. The presence of ER was shown in nine proliferative and ten secretory endometria and the presence of PR in three secretory and one proliferative endometria. ER and PR were localized by monoclonal antibodies, to the nuclei of cells, with the use of, respectively, peroxidase-antiperoxidase (PAP) and avidin-biotin-peroxidase complex (ABC) methods. Lymphoid cells were then delineated by decoration of their plasma membranes with the use of monoclonal antibodies to HLA-DR, leukocyte common antigen (LCA), Leu-4 (CD3), and IL-2 receptor molecules with the use of an ABC staining procedure. A group of cells in the lymphoid aggregates in endometrial stroma showing membranous staining for HLA-DR, LCA, and Leu-4 molecules had nuclear ER. IL-2 receptor-positive cells were rare in endometrium, and no PR-positive cells were found in lymphoid aggregates. Furthermore, HLA-DR and ER were expressed in the glandular and surface epithelium in the proliferative phase and in occasional glands in the basalis in the late secretory phase. The presence of an ER-positive lymphoid cell population in endometrial lymphoid aggregates suggests that these cells may serve as target cells for estrogen.     

Rheumatic Fever and Rheumatic Heart Disease: Cellular Mechanisms Leading Autoimmune Reactivity and Disease

Introduction  

Rheumatic fever (RF) is an autoimmune disease caused by the gram-positive bacteria Streptococcus pyogenes that follows a nontreated throat infection in susceptible children. The disease manifests as polyarthritis, carditis, chorea, erythema marginatum, and/or subcutaneous nodules. Carditis, the most serious complication, occurs in 30% to 45% of RF patients and leads to chronic rheumatic heart disease (RHD), which is characterized by progressive and permanent valvular lesions. In this review, we will focus on the genes that confer susceptibility for developing the disease, as well as the innate and adaptive immune responses against S. pyogenes during the acute rheumatic fever episode that leads to RHD autoimmune reactions.     

Cutaneous lesions in broiler chickens spontaneously affected with Marek's disease

A total of 91 8- to 9-week-old broiler chickens with Marek's disease (MD) skin tumours ("skin leukosis"), collected from 15 farms at the processing plants, were examined pathologically. Grossly, the skin lesions comprised various sizes and numbers of feather follicular nodules, which tended to fuse with each other as their size increased. Histologically, the lesions were classified into five types: type A was small lymphoid cell aggregates (LCA) consisting mostly of small lymphocytes with a few lymphoblasts and very rare mitotic figures; type B had large LCA consisting mainly of small lymphocytes with considerable numbers of lymphoblasts and very rare mitotic figures; type C was characterized by large coalesced LCA consisting almost equally of small lymphocytes and lymphoblasts with infrequent mitotic figures; type D exhibited very large coalesced LCA consisting mainly of lymphoblasts with some small lymphocytes and occasional mitotic figures; type E had very large coalesced LCA consisting almost completely of lymphoblasts with frequent mitotic figures. The histological MD cutaneous lesions were related to the size of gross skin nodules, the small feather follicular nodules consisted mainly of types B and C with type A, whereas large fused feather follicular nodules were composed mainly of types D and E. Nuclear inclusions were frequently found in the feather follicular epithelium in all skin nodules except for the largest fused ones. MD visceral lesions were more pronounced in birds having marked skin leukotic lesions. Feather pulp lesions (FPL) were more related to the visceral than the skin lesions; the constituent cells of FPL were compatible with those of the former lesions.     

Myocardial lysis in acute rheumatic fever followed by regeneration of cardiac muscle and origin of Aschoff bodies.

In acute rheumatic heart disease, lysis of cardiac muscle fibres with or without retention of sarcolemma is found to be the most damaging feature in many cases. In deeper myocardium the cellular lysis often forms anastomosing clefts or sinus-like spaces between surviving muscle bundles and in the outer portion of myocardium cellular lysis may leave the sarcolemma more or less intact. From lysing cardiac muscle fibres there arise dedifferentiated cells with remarkable potentiality for regeneration. For the origin of these dedifferentiated cells, which are often indistinguishable from lymphocytes, no mitosis is seen in cardiac muscle cells. The successive stages of development of muscle cell from these dedifferentiated cells within the remaining or newly formed sarcolemma have been observed in this study. This study infers that the increased number of fibrous septa, when seen, denotes the tracks of previous muscle degeneration and subsequent replacement of it with incomplete muscle regeneration and fibrous tissue formation. In an area of muscle lysis the origin of Aschoff bodies from these dedifferentiated cells has been followed. Ashoff bodies arising in this was behave as an abortive and atypical growth of muscle fibres in a nodular fashion specific to rheumatic fever.