Immunology

of Infective

Endocarditis

J. P. Phair and J. Clarke

P

ERSISTENT bacteremia is characteristic of infective endocarditis. The relationship of the immunologic consequencesof this antigenemia to the clinical and pathologic findings in endocarditis have been the subject of intensive investigation during the past 15 yr. The purpose of this review is to summarize the current status of our understanding of the interface of this infection and the immune response. Responseto microbial invasion in the intact host involves the cellular system, which constitutes host defense mechanisms: lymphocytes, macrophages, and polymorphonuclear neutrophils (PMN). For purposes of discussion, the activities of each of these cells are considered separately, but recent advances indicate that the function of these different cell types is closely interrelated. Thus, the specific immune response initially requires processingof antigen by macrophages. An antigen-directed response of both marrow-derived (9 cells) and thymic-dependent (T cells) lymphocytes ensues.This lymphocytic responseinvolves proliferation of clones of antigen-sensitive cells and secretion of their effector molecules. Immunoglobulins (antibodies) are secreted by B ceils and plasma cells: T cells mediate cellular immunity in concert with macrophages through production of lymphokines (macrophage inhibitory factor, etc.) and regulate B-cells function through “helper” and “suppressor” activity.‘,’ Antibody facilitates phagocytosis of bacteria by polymorphonuclear neutrophils through combination with antigenic determinants on the bacterial cell wall and receptors on neutrophil membranes.The adherence of bacteria to phagocytic cells, the first step of ingestion and bacterial killing, is also enhanced by the nonspecific humoral factors, which are the initial components of the complement cascade.3It is of interest to note that many of the complement components are secreted by macrophages.” HUMORAL

IMMUNITY

Immunoglobulins-the glycoproteins secreted by the B lymphocytes and their differentiated progeny, the plasma cells, in response to antigenie stimulation-comprise one major compo-

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Vol. XXII,

No. 3 (November/December),

nent of humoral immunity.” The humoral immune response is characterized by the presenceof specific immunoglobulins or antibodies in plasma and other body secretions. Immunoglobulins are a heterogenousgroup of plasma proteins subdivided into classes:IgG, IgA, IgM, IgD, and IgE. All immunoglobulins have the capability of combining with the specific substance (antigen) that elicits their production. Each immunoglobulin consistsof one or more basic units comprised of four polypeptide chains-two light and two heavy chains. The four chains are linked by noncovalent as well as four covalent disulfide bonds, which results in formation of two sites that combine with antigen. Each combining site is formed by the amino terminal end of one light and one heavy chain. IgG, IgD, and IgE are monomeric forms of this four-chain unit; IgM is a pentamer with ten polypeptide chains. Secretory IgA, found in body secretions, is a dimer held together by two other peptide chains, the secretory component and the J chain. Circulating IgA can be either dimeric or monomeric. The carboxy terminal end of the two heavy chains of the immunoglobulin molecule is termed the Fc or crystalizable fragment. The Fc fragment combines with cellular receptors, or complement, and mediates other biologic characteristics of immunoglobulins, such as placental passage. IgM is the predominant antibody in the early immune response.Blood group isoantibodiesand so-called “natural antibodies” to the gram-negative gut flora are of this class. IgC is the immunoglobulin found in highest concentration in the plasma and is secreted sequentially following From the Section of Infectious Disease, Department of Medicine, Northwestern University Medical School, Chicago. III. Supported in part by the Samuel J. Sackett Fund. Reprint requests should be addressed to J. P. Phair. M.D., Section of Infectious Disease, Department of Medicine, Northwestern University Medical School, Chicago. III. 60611. (1‘11979 bv Grune & Stratton, Inc. 0033-o&0/79/2203-0002$01.00/O

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IgM production during a primary immune response and with secondary stimulation. IgG provides antibody for promoting phagocytosis by PMN (opsonins), neutralizing bacterial toxins, and most virus. The Fc portion of IgG fixes complement (see below), but not as efficiently as IgM. IgA is demonstratable in the circulating blood but functions generally in body secretions to block access of antigen (virus, bacteria, allergens) to the internal melieu. IgD and IgE are mainly bound to cells, IgD to lymphocytes and IgE to mast cells, where they act as primary receptors for antigen. IgD binding of antigen probably serves as the primary event in production of immunoglobulins. IgE-antigen combination triggers the release of vasoactive substances from mast cells, which mediate allergic reactions. For a complete discussion of the immunoglobulins see Goodman and Wang.s A detailed description of the biology of complement, the second humoral system, and its relation to antibacterial mechanisms is beyond the scope of this article. Many reviews are current and available.4.6 Briefly, the major points of complement-antibody-bacterial interaction are outlined below. Fixation of the first component of complement (Clq) by either IgG- or IgM-coated bacteria results in activation of the classical complement pathway. In sequence, fixation of Clq by the FC fragment of antibody is followed by formation of an enzyme composed of Cl, C4. and C2. This complex enzymatically activates the third complement component C3. When deposited on bacterial cells walls, C3 acts as an opsonin and in turn leads to deposition of the remaining components, C5 through C9. These “late” components can lyse “serum-sensitive” bacteria. Circulating C3 can interact directly with bacteria. and substances such as cobra venom, in the presence of other precursor proteins, independent of antibody or C 1, C4, and C2. This means of activation of C3 is termed the alternative pathway and results in deposition of C5 through C9 on cell surfaces. It is important to note that inappropriate activation of the complement can have deleterious effects.6 With activation of the classical pathway, activated Cl ,4,2, leads to release of kinins; C3 and C5, activated either classically or via the alternative pathway, release anaphylatoxins. Both kinins and anaphylatoxins promote migration of PMN into inflammatory foci, the

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area of complement deposition. If this focus is :I glomcrulus, which has trapped a bacterialantibody-complement complex, the subsequent release of leukocytic enzymes leads to destruction of the basement membrane and nephritis. Three questions arise with regard to humoral immunity and endocarditis. First, can preexisting antibody acting with complement protect against valvular infection’? Second, is the humoral response altered in endocarditis? Third, does the humoral immune response contribute to the pathogenesis of the clinical syndrome of endocarditis? The majority of patients with endocarditis are infected with bacteria that are considered part of the “normal flora,” i.e., Streptococcus viridans, enterococci, or Staphylococcus aureus. Antibody specific for these organisms is present in the circulation of most individuals prior to the onset of endocarditis. It has been suggestedthat such preexisting antibody predisposesto valvular infection. This speculation is basedon the observations that endocarditis can be established in a varying percentage of experimental animals following either multiple intravenous innoculations of bacteria or establishment of another focus of infection prior to intravenous challenge. Other studies have noted that a nonspecific hyperimmune state predisposedvalves to colonization following an intravenous challenge. It is proposed that the mechanism of this predisposition is agglutination of bacteria by antibody, resulting in presentation of a greater inoculum to the previously damaged endothelial surface. Sande concluded in his review of these experiments that prolonged exposure of the valve to bacteria was more critical than the effects of antibody in the development of endocardial infection.’ The protective effect of serum bactericidal factors (complement) in the pathogenesis of endocarditis due to aerobic enteric bacilli also has been investigated. Durack has reported that catheter-induced experimental endocarditis was produced in 90% of rabbits challenged with serum-resistant E. coli and in only 1I%, of rabbits inoculated with serum-susceptiblestrains of this organism. Rabbits deficient in the sixth component of complement, and therefore unable to lyse bacteria, however. were susceptible to infection with serum-sensitive strains. It has been postulated that this complement-dependent system may prevent development of endocarditis

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during gram-negative bacteremia, an uncommon cause of endocarditis.8 The specific antibody response to the persistent bacteremia of infective endocarditis has been characterized in investigations conducted by Quie and coworkers.’ Techniques for demonstrating specific antibodies included agglutination and complement fixation. Such antibodies can be of the IgM, IgG, or IgA class of immunoglobulins.” Agglutinating and complementfixing antibody are not preferentially associated with a specific immunoglobulin class, and the distribution between the 7s and 19s fractions did not correlate with the duration of illness9 Opsonic titers are higher in sera of patients with infective endocarditis than in control sera, have been demonstrated to be specific in absorption studies using the infecting bacteria, and are both heat labile and heat stable. The heat-labile factors (complement) in normal serum are more effective opsonins than the heat-stable component (antibody) but are not essential for promotion of phagocytosis of S. aureus and other gram-positive cocci. In contrast, the specific heat-stable opsoninsin “immune” sera obtained from patients with endocarditis supported phagocytosis more efficiently. Eradication of the intravascular focus of infection by polymorphonuclear leukocytes plus opsonin, however, is prevented presumably by the inability of the phagocytes to reach opsonized bacteria deeply lodged in the fibrin threads of the thrombus, which serves as the nidus of infection on the valve.’ ’ In addition to the specific humoral response that occurs in endocarditis patients, a nonspecific generalized hypergammaglobulinemia develops as in many chronic and subacute infections. This is manifest by elevations of titers of antibody to a number of noninfecting microorganismsand autoantibodies, including anti-heart antibodies, antiglobulins, and cryoglobulins (cold precipitable) complexes, which can be demonstrated in patients with prolonged endocarditis.‘* ” Production of such nonspecific antibodies is not associatedwith familial or an individual predisposition to “autoimmune” disease or with a specific infecting bacteria, but correlates closely with an illness that is usually longer than 6 wk.lh A recent study has suggested that antiglobulins also can be demonstrated in sera of patients with acute endocarditis, but this finding is open to question, as this was studied in drug

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addicts who have a high prevalence of autoantibodies, especially antiglobulins.” Antiglobulins (antibodies that react with autologous gammaglobulin) can be detected in sera by a number of techniques.” Williams suggested that the specificity of antiglobulins found in endocarditis sera was narrower than that of antiglobulins demonstrable in sera from patients with rheumatoid arthritisI a finding confirmed by Phair et a1.19Thus, only 9 of 23 sera that reacted with latex particles coated with aggregated IgG also reacted with sheepred cells coated with rabbit sheeperythrocyte sera, and 1 of 22 reacted with human erythrocytes coated with anti-Rh antibody. This restricted reactivity may be evidence that the antiglobulins in endocarditis are specific anti-antibodies, that is, antibody directed at the antibacterial antibody. The titer of antiglobulins can be lowered by absorption of the serum with infecting organisms but not by absorption with noninfecting bacteria of the same species.‘gThis is true even in the presenceof high titers of agglutinating antibody specific for the noninfecting bacteria in whole sera or the 1gG fraction of the sera. Incubation of the isolated 1gM antiglobulin with the infecting bacteria did not alter the antiglobulin titer. This suggeststhat the infecting bacteria do not combine with antiglobulins directly and that antiglobulins in endocarditis are produced in responseto IgG that has been altered antigenitally by combination with antigen (the infecting microorganism) so as to becomeimmunogenic.*’ An alternative explanation of the development immunogenicity of IgG could be a change in the carbohydrate composition of immunoglobulins induced directly by bacterial factors.” Antiglobulins can be produced experimentally by intravenous inoculation of rabbits with streptococci.“’ Antiglobulin produced in this manner can circulate as a mixed cryoglobulin. consisting of an electrophoretically homogenous IgG, the specific antibacterial antibody, in combination with the 1gM antiglobulin.’ With appropriate chemotherapy, clearance of the bacteria, and sterilization of the valvular lesion, the antiglobulins disappear.” Return of the antiglobulins, even in the absence of bacteremia, has been noted to herald a relapse of the endocarditis. Whether or not antiglobulins fulfill a protective function or are deleterious clinically in endocarditis is unclear. Davis has demonstrated in

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vitro that a mixed cryoglobulin (antiglobulin plus IgG) can inhibit the polymorphonuclear leukocyte response to chemotaxtic factors.24 In addition, IgM antiglobulins, when combined with the Fc fragment of opsonic antibody (IgG), block the fixation of the first component of complement, inhibiting phagocytosis of the bacterial-antibody complex.” In contrast to these results, which represent detrimental effects on host defense functions, are studies that indicate that although IgM antiglobulin blocks fixation of complement on the Fc fragment of IgG, IgM itself represents a major site of enhanced complement attached. Thus, fixation of a IgM antiglobulin by an antigen-IgG complex could convert weak complement-fixing aggregates into complexes associated with greater complement lixation.2’ This may enhance the inflammatory response by promotion of phagocytosis of soluble aggregates of IgG.” The presence of antiglobulins may play a role in the development of the renal complications of endocarditis (see below). Infusion of serum containing antiglobulins increases the severity of nephrotoxic serum-induced nephritis in rats.” In patients with glomerulonephritis due to other causes, such as systemic lupus erythematosus (SLE), membranoproliferative glomerulonephritis, and Goodpasture’s syndrome, the severity of the renal disease has been reported to correlate with circulating antiglobulin levels.” Renal tissue of patients with severe glomerulonephritis reacted with aggregated IgG, thus implying deposition of antiglobulins in the kidneys. Unfortunately, renal tissue from only one patient was treated so as to rule out binding of aggregates by the first component of complement, which also can combine with altered IgG. In addition, there was a poor correlation between renal tissue staining for antiglobulins and the presence of antiglobulins in the circulation. The authors felt that there was no evidence that antiglobulins increased glomerular deposition of immunoglobulins or contributed to glomerular damage. Finally, the presence or absence of circulating antiglobulins in patients with endocarditis has not correlated with the development of hypocomplementeric immune complex nephritis.14 Another autoantibody that has been demonstrated in the sera of patients with infective endocarditis reacts with myocardium.‘3 Anti-

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heart antibodies are demonstrable by use of an indirect technique using fluorescenated antihuman rabbit antisera to detect serum antibody bound to human myocardial tissue. Two types of fluorescent staining are noted: sarcolemmal and subsarcolemmal. Anti-heart antibody was detected in sera of 9 of 13 patients with endocarditis, 1 of 25 patients with coronary artery disease, and I of 41 healthy controls. Antibody was generally of the IgG class. Antiglobulins were present in 4 of the 13 endocarditis patients and generalized hypergammaglobulinemia in the majority. Seven of eight patients with clinical heart failure had anti-heart antibody demonstrable. Cure of the endocarditis results in disappearance of this antibody from the serum. The relevance of anti-heart antibodies to the clinical manifestation of infective endocarditis is open to question. Anti-heart antibodies are not cytotoxic, in vitro or in vivo. Talano has postulated that the antibody develops with release of antigens secondary to muscle damage and is not involved in the pathogenesis of myocradial lesions.” Other immunologic alterations noted in patients with endocarditis include elevated total hemolytic complement in the absence of nephritis and elevated immunoconglutinin.‘4 lndividu-’ als receiving multiple immunizations, another situation of intense antigen stimulation, also develope increases in immunoconglutinin and/or antiglobulin titers. These elevations usually do not occur in the same individual, and immunoconglutinin appears to rise earlier than do antiglobulin titers.j’ Immunoconglutinins are IgM antibodies3’ directed at the third and fourth component of complement that have been fixed by an antigen-antibody complex. High titers of immunoconglutinins in endocarditis are noted especially in patients with nephritis.lJ The biologic relevance of immunoconglutinin is not clear. However, passive administration of this IgM antibody enhances resistance of rabbits to experimental infection and clearance of bacteremia.” The B-cell hyperresponsiveness in infective endocarditis. which is manifest by hypergammaglobulinemia, autoantibody production, and nonspecific antibody rises, may represent stimulation of the immune system by chronic infection or loss of suppressor cell activity. Intense immunization of chickens has been documented to

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induce polyclonal hyperimmunoglobulinemia.34 Moticka has demonstrated that this response is both thymus (T cell) and bursa (B cell) dependent and will not occur if the animal is tolerant (unresponsive) to the antigen. The immunoglobulin produced as a result of intense stimulation contains antibody to noncrossreacting antigens that had previously immunized the birds. He postulates that the mechanism involves release of lymphokines by T cells, which nonspecifically stimulate the B cells to produce antibody for which they are programmed. Loss of suppressor cell activity, leading to uncontrolled immunoglobulin production, has been documented in NZB mice that manifest autoimmune phenomenon analogous to SLE.35 Waldman also has presented evidence of similar defect in regulatory cells in patients with autoimmune disease,36 however, no documentation of suppressor cell activity in endocarditis is available. IMMUNE

COMPLEX

NEPHRITIS

Renal disease is commonly associated with bacterial endocarditis. Immune mechanisms play an important role in the pathogenesisof this problem, however. renal emboli, both bland and septic, are also significant causative factors. Renal complications are the most significant immunologic manifestations of infective endocarditis and early descriptions of the disease included patients with renal insufficiency. The reported incidence of mild renal involvement depends on the population studied and criteria utilized in the diagnosis. As judged by hematuria, the prevalence of renal disease in patients with endocarditis ranges from 37%’ to 93%. Hematuria was present in 25% of Lerner and Weinstein’s patients.37Using light microscopy in the study of autopsy material, Bell3Rreported 82.4% of patients with primary endocarditis displayed histologic changes. The recent investigation of Morel-Maroger et al.39 employed routine and immunofluorescent (IF) techniques and documented abnormalities in nine consecutive renal biopsiesof patients with endocarditis. There are three major renal lesions found in patients with endocarditis. Renal infarction, which has been described in up to 56% of patients in an autopsy series3’ is the major pathogenic factor that doesnot have an immunologic basis. It is currently postulated that both

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focal “embolic” glomerulonephritis and proliferative glomerulonephritis are secondary to immunologic events. The evidence for this postulate is derived from studies of human material and animal models. Obtaining human renal tissue for study requires an invasive procedure-the needlebiopsy-and the technique required to demonstrate and identify immune complexes, consisting of bacterial antigen, antibody, and complement, are not universally available. When renal tissue is available, the investigator is limited to evidence obtained at one time and must extrapolate to reconstruct a dynamic process. Animal investigations have been required to obtain an understanding of the evolution of this lesion. In reviewing over 2000 patients with a broad spectrum of immune disease, Dixon and Wilson4” have described three general patterns of renal disease.Antiglomular basement membrane (GBM) nephritis accounted for 7%; in this pattern, IF staining demonstrates sharp linear deposition of immunoglobulin (Ig) and occasionally complement along the GBM. “Complement only” nephritis accounts for 13% of biopsies.and IF reveals granular staining of late complement components, Immune complex (IC) nephritis was present in the remaining 80% of the renal biopsiesand included patients with endocarditis. Antigen, antibody, and both early and late complement components and present in these lesions. The lesion of IC nephritis have wide irregular boundaries and a granular pattern along the GBM and often in the mesangium. The pathogenesis of this lesion involves a number of humoral and cellular components, as summarized by Wilson and Dixon. Antigen and antibody combine to form an IC, which in turn results in the releaseof vasoactive agents, including serotonin, from platelets. The subsequent alteration in the permeability of vessel walls enhances trapping of IC in endothelium. The complement components activated by fixation with the antigen-antibody complex attract polymorphonuclear leukocytes that degranulate, releasing enzymes that can damage vascular endothetium and GBM. The diagnosisof IC nephritis in patients with infective endocarditis should be considered in azotemic patients with proteinuria or an abnormal sediment. It must be emphasized that compromised cardiac output, emboli. and anti-

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biotic-induced nephritis can all adversely affect renal function. Definitive documentation of IC nephritis requires identification of circulating immunocomplexes (CIC), confirmation of low serum C, and detection of IC components on renal biopsy. Bayer et al. have recently described CIC in 28 of 29 patients with infective endocarditis.4’ Immune complexes formed in antibody excess (patients with subacute or chronic endocarditis) are large. These complexes are often identified as subendothelial or mesangeal deposits.4’ Complexes formed in modest antigen excess (acute endocarditis) are smaller and frequently localize as subepithelial deposits and have been described in acute staphylococcal endocarditis.43,44 In the early lesions of IC nephritis, histologic lesions are not pronounced, but deposition of Ig and C is prominent; IgG is more commonly noted than IgA or IgM. Eleven recent articles have described a total of 33 endocarditis patients in whom immunofluorescent studies were performed.39,4’m50 Complement was detected most frequently (23 of 26 patients examined) followed by IgG (15 of 26), IgM (7 of 17) and IgA (3 of 17). As expected, proliferative lesions occur near areas staining for C components.44 In older lesions, the histology shows increasing damage, and staining for Ig and C is less obvious.” Morel-Maroger demonstrated positive C3 staining in four patients with no visible Ig,39 and animal studies have suggested that C in IC nephritis persist longer than Ig. Severe renal insufficiency is not uncommon in patients dying with subacute infective endocarditis. Bell reported significant renal insufficiency in 15 of 108 patients3’ and Villareal in 23 of 100 autopsied patients with subacute bacterial endocarditis.52 The lesions may be acute or chronic, focal or diffuse. These patients reportedly have’ less fever, are usually normotensive, and have an unusually high rate of negative blood cultures.37 Antibiotic treatment of the underlying endocarditis is the cornerstone of successful therapy of immune complex nephritis due to endocarditis. Other therapeutic modalities are of unproven value. Gorlins3 noted that the incidence of clinical renal insufficiency fell from the rate of 25% 35% to 10% of patients with endocarditis after the introduction of penicillin. The evolution of the renal lesion is arrested with successful antibiotic therapy, and renal insufficiency is usually reversible, although histologic changes may

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persist for months. Despite antibiotic therapy, an occasional patient will die of progressive renal failure. OTHER POSSIBLE IMMUNOLOGIC MANIFESTATIONS OF ENDOCARDITIS

It has been postulated that Roth’s spots and the vascular lesion of the pads of the fingers, Osler’s nodes,are due to hypersensitivity angitis. The immunopathogenic mechanism proposed is analogous to that underlying the glomerulonephritis discussed above. However, to date, there has been a failure to demonstrate Ig or components of complement in these lesions. Furthermore, biopsies obtained early in the evolution of Osler’s nodesin patients with acute endocarditis have revealed, with culture and histologic examination, evidence of bacterial emboli.s4 No definitive studies have delineated the pathogenesisof Roth’s spots. although histologic studies indicate that microemboli are possibly responsiblefor these retinal lesions.55 CELLULAR

IMMUNITY

In contrast to the intensive investigations of the humoral immune responsesin endocarditis, there have been few reports of studies of cellular immunity or function of T lymphocytes and macrophagesin this infection. There is evidence that the mononuclear phagocytic system is stimulated. Peripheral monocytosis has long been noted, and splenomegaly is a common physical finding. The mechanism of this monocytosis is unknown. However, Metcalf and coworkers have demonstrated that colony-stimulating factor (CSF), a naturally occurring glycoprotein that stimulates an increase in the number of progenitors of granulocytes and monocytes in marrow and spleen, increases following immunization.56 He has further demonstrated a sustained increases in serum and urine concentrations of CSF during active infections. Kauffman et al. have reported that lymphocyte DNA synthesis in responseto exposure to the mitogen, phytohemagglutinin, was reduced in 9 of 16 patients with endocarditis. The doseresponse curve to increasing concentrations of the mitogen was similar to that of controls, and there was gradual improvement in lymphocyte responsivenesswith treatment of endocarditis. The depressed lymphocyte response did not correlate with the presence of circulating antiglobulins, hypergammaglobulinemia, or elevated

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Lu-macroglobulins; the latter are known to interfere with lymphocyte responses to nonspecific mitogens. The percentage of the lymphocytes that react with sheep red blood cells (T cells) was normal.3’ Similar decreased lymphocyte reactivity to phytomitogens has been noted in a number of acute and chronic infections.57m6’ T-cell hyporeactivity in chronic fungal infection has been shown to be due to suppressor T-cell activity.6’ The media in which peripheral blood lymphocytes were cultured contained a soluble inhibitor of lymphocyte reactivity. This inhibitor. which has a molecular weight of 1000, was presumably a product of the suppressor T cells and did not alter B-cell function. The mechanism underlying alteration of lymphocyte reactivity in endocarditis remains obscure. CONCLUSION

Endocarditis is generally the result of colonization of an intravascular locus by indigenous bacteria. Specific antibody does not prevent this infection, and the organisms are generally protected from phagocytes by the structure of the infected thrombus. Except for the bactericidal effects of complement on specific aerobic gram-negative bacteria, humoral factors appear to play no role in preventing or controlling this infection. In responseto the continuous release of bacteria into the blood stream, there is an enhanced production of specific antibacterial antibodies and a generalized nonspecific responseas manifested by autoantibodies. Cellular immunity, as in other acute and chronic infections, is probably depressed.One of the major complications of endocarditis, glomerulonephritis, appears to result from the formation of immune complexes formed of bacteria (bacterial antigens) antibody and complement. Whether either clinical benefit derives from or further complications result from the altered immune response,however, is far from clear. REFERENCES I. Greaves MF. Owen JJT. Raff MC: T and B Lymphocytes: Origin Properties and Roles in Immune Responses. Amsterdam, Excerpta Medica, 1973 2. Cell mediated immunity and resistance to infection. Technical Report Series No. 519. Geneva, World Health Organization, 1973 3. Stossel TP: Phagocytosis. N Engl J Med 290:7 17-723. 1974 4. Milller-Eberhard HJ: Complement. Ann Rev Biochem 44697-724. 1915

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5. Goodman JW. Wang AC: Immunoglobulin, in Fudenberg HH, Stites DP. Caldwell JL, et al (eds): Structure and Diversity in Basic and Clinical Immunology (ed 2). Los Altos, Calif, Lange Medical, 1978 6. Jacob HS: Granulocyte-complement interaction: A beneficial antimicrobial mechanism that can cause disease. Arch Intern Med 38:461-463. 1978 7. Sande MA: Experimental endocarditis, in Kaye D (ed): Infective Endocarditis. Baltimore, University Park Press, 1976 8. Durack DT, Beeson PB: Protective role of complement in experimental endocarditis. Infect lmmunol 15:2 I332 17. 1977 9. Laxdal T, Messner RP, Williams RG, et al: Opsonic agglutinating and complement-fixing antibodies in patients with subacute bacterial endocarditis. J Lab Clin Med 71:6388653. I968 IO. Lunn JS, Bunn PA: lmmunoglobulin responses to bacterial endocarditis. Antimicrob Agents Chemother 5:.5963, 1965 I I. Durack DT: Experimental bacterial endocarditis. IV. Structure and evaluation of very early lesions. Br J Path01 ll5:81. 1975 12. Bacon PA, Davidson C. Smith B: Antibodies in subacute bacterial endocarditis. Q J Med 172:537-550, 1974 13. Das SK, Cassidy JT: Importance of heart antibody in infective endocarditis. Arch Intern Med 137:591-593. 1977 14. Williams RG, Kunkel HG: Rheumatoid factor, complement and conglutinin aberrations in patients with subacute bacterial endocarditis. J Clin Invest 41:666675. 1962 15. Hurwitz D, Quismoro FP, Triou GJ: Cryoglobulins in patients with infectious endocarditis. Clin Exp lmmunol 19:131-141,1975 16. Messner RP. Laxdal T, Quie PG. et al: Rheumatoid factors in subacute bacterial endocarditis: Bacterium, duration of disease or genetic predisposition. Ann Intern Med 68:746-756. I968 17. Sheagren JN. Tuazon CU, Griffin C. et al: Rheumatoid factor in acute bacterial endocarditis. Arthritis Rheum 19:8877890, 1976 18. Wailer M: Correlation between diagnosis and results of serologic tests for antiglobulin antibodies. Am J Med 54:731-734.1973 19. Phair JP. Klippel J, MacKenzie MR: Antiglobulin in endocarditis. Infect Immunol 5:24-26, 1972 20. Williams RC Jr, Mellby OJ, Kronvall G: Antigamma globulin and chronic infection: Comparative studies of the immune response to various bacteria and gamma globulin preparations. Infect Immunol6:3 166323. 1972 21. Herd ZL: Antiglobulins and cryoglobulins in rabbits producing homogeneous streptococcal antibodies. Immunology 25:9233930.1973 22. Abruzzo JL. Christian CL: The induction of a rheumatoid factor like substance in rabbits. J Exp Med I 14:791806. 1961 23. Herd ZL: Experimental cryoglobulinaema. Production and properties of streptococcus-induced rabbit cryoglobulins. Immunology 25:931-939, 1973 24. Davis AT. Grady PG, Shapira E. et al: PMN chemotactic inhibition associated with a cryoglobulin. J Pediatr 90:2255229, 1977 25. Messner RP. Laxdal T. Quie PG. et al: Serum opson-

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in. bacteria and polymorphonuclear leukocyte interactions in subacute bacterial endocarditis: Anti-a-globulin factors and their interaction with specific opsonins. J Clin Invest 47:110991120. 1968 26. Schmid FR. Roitt IM, Rocha MJ: Complement fixation by a two-component antibody system: lmmunoglobulin G and immunoglobulin M anti-globulin (rheumatoid factor). J Exp Med I32:673696. 1970 27. Tesar JT. Schmid FR: Conversion of soluble immune complexes into complement fixing aggregates by IgMRheumatoid factor. J Immunology 105: l206- I 2 14. 1970 28. McCormick JN. Day J. Morno CJ. et al: The potentiating effect of rheumatoid arthritis serum in the immediate phase of nephrotoxic nephritis. Clin Exp lmmunol 4: 17728, 1969 29. Rossen RD. Reisberg MA, Sharp JT. et al: Antiglobulins and glomerulonephritis: Classification of patients by the reactivity of their sera and renal tissue with aggregated and native human IgG. J Clin Invest 56:427-437. 1975 30. Talano JV: Importance of myocardial antibodies in heart disease. Arch Intern Med 137:570-575, 1977 3 I. Aomer KAT. Salo OP: Rheumatoid factor and immunoconglutinin response following various vaccinations. Proc Sot Exp Med 124:229-233, 1967 32. Lachman PJ, Liske R: The preparation and properties of alexinated intermediates that react with conglutinin in guinea pig complement. Immunology I 1:2433254. 1966 33. Parappally ND, Ingram DC: Role of immunoconglutinin in resistance to infection. Immunology 25:5233530, 1973 34. Moticka EJ: Cellular basis and nature of the polyclonal hyperimmunoglobulinemia induced by antigenic challenge. Cell lmmunol 19: 32-40, 1975 35. Stutsman 0: Cell mediated immunity and aging. Fed Proc 33:2028-2032. 1974 36. Waldman TA, Broder S: Suppressor cells in the regulation of the immune response, in Schwartz RS (ed): Clinical Immunology, vol. 3. New York, Grune & Stratton, 1977 37. Lerner PI, Weinstein L: Infective endocarditis in the antibiotic era. N Engl J Med 274:259-266, 1966 38. Bell ET: Glomerular lesions associated with endocarditis. Am J Path01 8:639-663, 1932 39. Morel-Maroger L, Sraer JD. Hereman G, et al: Kidney in subacute endocarditis: Pathological and immunofluorescence findings. Arch Pathol 94:205-213. 1972 40. Dixon FJ, Wilson CB: Recent advances in immunology of glomerulonephritis. Proceedings of the 6th International Congress on Nephrology. Florence. 1976. Basel, Karger, 1976, pp 60-68 41. Bayer AS, Theofilopoulos AN, Eisenberg R. et al: Circulating immune complexes in infective endocarditis. N Engl J Med 205: 1500-I 505, 1976 42. Boulton-Jones JM, Sissons JGP, Evans DJ, et al: Renal lesions of subacute infective endocarditis. Br Med J l:ll-14, 1974

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43. Guttman RA, Striker GE, Gelliland BC, et al: The immune complex glomerulonephritis of bacterial endocarditis. Medicine 5 I : I -25, 1972 44. Keslin MH. Messner RP, Williams RC: Glomerulonephritis with subacute bacterial endocarditis. Arch Intern Med 132:5788581, 1973 45. Levy RL. Hong R: The immune nature of subacute bacterial endocarditis (SBE) nephritis. Am J Med 54:645652, 1973 46. Perez GO, Rothtield N. Williams RC: Immunecomplex nephritis in bacterial endocarditis. Arch Intern Med 136:334-336. 1976 47. Tu WH, Shearn MA, Lee JC: Acute diffuse glomerulonephritis in acute staphylococcal endocarditis. Ann Intern Med 71:3355341. 1969 48. Berman L. Meyers AM: Glomerulonephritis. nephrotic syndrome and bacterial endocarditis. South Afr Med J 46850-85 I, 1972 49. McIntosh RE, Tinglof B, Kaufman D. et al: Immunohistology in renal disease. J Med 159:358-390. 197 I 50. Michael AF. IHerdman RC. Fish AJ, et al: Chronic membranoproliferative glomerulonephritis with hypocomplementemia. Transplant Proc I :9255932, 1969 51. Wilson CB: Diagnosis of immunopathologic renal injury. Proceedings of the 6th International Congress on Nephrology. Florence, 1976. Basel. Karger, 1976. pp 740147 52. Villarreal H. Sokoloff L: The occurence of renal insufficiency in subacute bacterial endocarditis. Am J Med Sci 220:655-661, 1950 53. Gorlin R. Favour CB, Emery FJ: Long term follow up study of penicillin treated subacute bacterial endocarditis. N Eng J Med 242:995-1001, 1950 54. Alpert JS. Kraus HF. Dalen JE. et al: Pathogenesis of Osler’s nodes. Ann Intern Med 85:471-473, 1976 55. Kennedy JE, Wise GN: Clinicopathological correlation of retinal lesions. Subacute bacterial endocarditis. Arch Ophthalmol74:658-662. 1965 56. Metcalf D: Acute antigen induced elevation of serum colony stimulating factor (CSF) levels. Immunology 21:427436. I97 I 57. Kauffman CA, Worth PM, Phair JP: Response to phytohemagglutinin in patients with infective endocarditis-Abstract presented at the 15th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, D.C., 1975 58. Kauffman CA, Linnemann CC, Schiff GM, et al: The effect of viral and bacterial pneumonia on cell mediated immunity in humans. Infect lmmunol 13:78-83, I976 59. Kantor FS: Infection, anergy and cell mediated immunity. N Engl J Med 292:6299634. 1975 60. Dwyer JM, Bullock WE, Fields JP: Disturbance of the blood T and B lymphocytes ratio in lepromatous leprosy: Clinical and immunological correlations. N Engl J Med 228:1036-1039, 1973 61. Stobo JD, Paul S, Van Scoy RE. et al: Suppressor thymus derived lymphocytes in fungal infection. J Clin Invest 57:319-328, 1976

Immunology of infective endocarditis.

Immunology of Infective Endocarditis J. P. Phair and J. Clarke P ERSISTENT bacteremia is characteristic of infective endocarditis. The relationsh...
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