Immune Response in Kidney Disease PDF

CELULLAR IMMUNE RESPONSE IN KIDNEY DISEASE JULIA HARTATI, DR., M.KES MICROBIOLOGY DEPARTMENT FAKULTAS KEDOKTERAN UNISBA IMMUNE RESPONSE  Microorganisms that cause disease and produce damage, or pathology, to ti...

CELULLAR IMMUNE RESPONSE IN KIDNEY DISEASE JULIA HARTATI, DR., M.KES MICROBIOLOGY DEPARTMENT FAKULTAS KEDOKTERAN UNISBA IMMUNE RESPONSE  Microorganisms that cause disease and produce damage, or pathology, to tissues are referred to as pathogenic microorganisms, or simply pathogens. The agents that cause disease fall into five groups: viruses, bacteria, fungi, protozoa, and helminths (worms). Pathogens can be found in various compartments of the body, where they must be combated by different host Anatomic defense mechanisms. Intracellular phases of pathogens such as viruses are not barriers accessible to these mechanisms; instead, the infected cell and initial is attacked by the NK cells of innate immunity or by the cytotoxic T cells of adaptive immunity. chemical Activation of macrophages as a result of NK-cell or T-cell defenses activity can induce the macrophage to kill pathogens that are living inside macrophage vesicles. Pathogens can damage tissues in a variety of different ways Many barriers prevent pathogens from crossing epithelia and colonizing tissues The spread of a pathogen is often initially countered by an inflammatory response that recruits more effector cells and molecules of the innate immune system out of the blood and into the tissues, while inducing clotting in small blood vessels further downstream so that the microbe cannot spread through the circulation.  The cellular responses of innate immunity act over several days. During this time, the adaptive immune response may also begin if antigens derived from the pathogen are delivered to local lymphoid tissues by dendritic cells While an innate immune response may eliminate some infections, an adaptive immune response can target particular strains and variants of pathogens and protect the host against reinfection by using either effector T cells or antibodies to generate immunological memory Complement Activation Pathways of complement activation  The classical pathway is one of the major effector mechanisms of the humoral arm of adaptive immune responses. Innate immune system soluble proteins called pentraxins, can also bind C1q and initiate the classical pathway. The alternative pathway, is triggered when a complement protein called C3 directly recognizes certain microbial surface structures, such as bacterial LPS.  MBL is a member of the collectin family with a hexameric structure similar to the C1q component of the complement system. After MBL binds to microbes, two zymogens called MASP1 (mannose-associated serine protease 1, or mannan-binding lectin-associated serine protease) and MASP2, with similar functions to C1r and C1s, associate with MBL and initiate downstream proteolytic steps identical to the classical pathway The complement system is an essential component of innate immunity, and patients with deficiencies in C3 are highly susceptible to recurrent, often lethal, bacterial infections. Genetic deficiencies in MAC formation (the terminal product of the classical pathway) increase susceptibility to only a limited number of microbes, notably Neisseria bacteria, which have thin cell walls that make them especially susceptible to the lytic action of the MAC.  The leukocytes and plasma proteins normally circulate in the blood and are recruited to sites of infection and injury, where they perform various effector functions that serve to kill microbes and begin to repair tissue damage. THE Typically, the most abundant leukocyte that is INFLAMMATORY recruited from the blood into acute inflammatory sites is the neutrophil, but blood monocytes, which RESPONSE become macrophages in the tissue, are increasingly prominent over time and may be the dominant population in some reactions. Among the important plasma proteins that enter inflammatory sites are complement proteins, antibodies, and acute-phase reactants. These changes include increased blood flow into the tissue due to arteriolar dilation, increased adhesiveness of circulating leukocytes to the endothelial lining of venules, and increased permeability of the capillaries and venules to plasma proteins and fluid. All of these changes are induced by cytokines and small-molecule mediators initially derived from resident cells in the tissue, such as mast cells, macrophages, and endothelial cells, in response to PAMP or DAMP stimulation. As the inflammatory process develops, the mediators may be derived from newly arrived and activated leukocytes and complement proteins. Acute inflammation can develop in minutes to hours and last for days. Chronic inflammation is a process that takes over from acute inflammation if the infection is not eliminated or the tissue injury is prolonged. It usually involves recruitment and activation of monocytes and lymphocytes. Chronic inflammatory sites also often undergo tissue remodeling, with angiogenesis and fibrosis Phagocytosis and intracellular destruction of microbes Functions of macrophages Local and systemic actions of cytokines in inflammation  One circumstance in which this happens is when harmful immunologically mediated hypersensitivity reactions known generally as allergic reactions occur in response to inherently harmless ‘environmental’ antigens such as pollen, food, and drugs. Historically, hypersensitivity reactions due to immunological responses were classified by Gell and Coombs into four broad types, of which type I hypersensitivity reactions represented immediate-type Hypersensitivity allergic reactions mediated by IgE antibodies, with mast- cell activation the major final effector mechanism. Type II and III hypersensitivity responses were defined as those that were driven by antigen-specific IgG antibodies, the final effector mechanism being complement (type II) or FcR-bearing cellular effectors (type III). Finally, type IV hypersensitivity responses were depicted as being driven by cellular effectors, including lymphocytes and a variety of myeloid cell types  Non-IgE dependent drug-induced hypersensitivity reactions in susceptible individuals occur by binding of the drug to the surface of circulating blood cells. Non-IgE- Antibody-mediated destruction of red blood cells (hemolytic anemia) or platelets (thrombocytopenia) mediated can be caused by some drugs, including the β- lactam antibiotics penicillin and cephalosporin allergic Systemic disease caused by immune-complex formation can follow the administration of large diseases quantities of poorly catabolized antigens Hypersensitivityreactions can arise following treatment with soluble antigens such as animal antisera. The pathology is caused by the deposition of antigen:antibody aggregates, or immune complexes, in particular tissues and sites. Immune complexes are generated in all antibody responses, but their pathogenic potential is determined, in part, by their size and by the amount, affinity, and isotype of the responding antibody. Larger aggregates fix complement and are readily cleared from the circulation by the mononuclear phagocyte system. However, the small complexes that form when antigen is in excess tend to be deposited in blood vessel walls. There they can ligate Fc receptors on leukocytes, leading to leukocyte activation and tissue injury  Pathological immune-complex deposition is seen in other situations in which antigen persists In these situations, the replicating pathogen is Immune continuously generating new antigen in the presence of a persistent antibody response, with the consequent formation of abundant immune complexes. complex These are deposited within small blood vessels and result in injury in many tissues and organs, including the skin, disease kidneys, and nerves The immune complexes bind Fc receptors such as FcγRIII in kidney on mast cells and other leukocytes, generating a local inflammatory response and increased vascular permeability. Fluid and cells, especially polymorphonuclear leukocytes, then enter the site of inflammation from local blood vessels. The immune complexes also activate complement, leading to the production of the complement fragment C5a. This is a key participant in the inflammatory reaction because it interacts with C5a receptors on leukocytes to activate these cells and attract them to the site of inflammation Recruitment and activation of C5a receptor-bearing leukocytes leads to tissue injury, sometimes resulting in frank necrosis the C3a, C4a, and C5a complement split products are anaphylatoxins that cause localized mast-cell degranulation and consequent increase in local vascular permeability. C3a, C5a, and C5b67 are also chemotactic factors for neutrophils, which can accumulate in large numbers at the site of immune-complex deposition. Larger immune complexes are deposited on the basement membrane of blood vessel walls or kidney glomeruli, whereas smaller complexes may pass through the basement membrane and be deposited in the sub epithelium. The type of lesion that results depends on the site of deposition of the complexes The C3b complement component acts as an opsonin, coating immune complexes. A neutrophil binds to a C3b-coated immune complex by means of the type I complement receptor, which is specific for C3b. Because the complex is deposited on the basement membrane surface, phagocytosis is impeded, so that lytic enzymes are released during the unsuccessful attempts of the neutrophil to ingest the adhering immune complex. Further activation of the membrane-attack mechanism of the complement system can also contribute to the destruction of tissue. In addition, the activation of complement can induce aggregation of platelets, and the resulting release of clotting factors can lead to formation of microthrombi. Antigen-antibody complexes are produced during normal immune responses, but they cause disease only when they are produced in excessive amounts, are not efficiently cleared, and become deposited in tissues. Small complexes are often not phagocytosed and tend to be deposited in vessels more than large complexes, which are usually cleared by phagocytes. Complexes containing cationic antigens bind avidly to negatively charged components of the basement membranes of blood vessels and kidney glomeruli. Such complexes typically produce severe and long- lasting tissue injury.  Capillaries in the renal glomeruli and synovia are sites where plasma is ultrafiltered (to form urine and synovial fluid, respectively) by passing through specialized basement membranes, and these locations are among the most common sites of immune complex deposition. However, immune complexes may be deposited in small vessels in virtually any tissue.  Deposits of antibody and complement may be detected in the vessels, and if the antigen is known, it is possible to identify antigen molecules in the deposits as well Immune complexes deposited in vessel walls and tissues activate leukocytes and mast cells to secrete cytokines and vasoactive mediators. These mediators may cause more immune complex deposition in vessel walls by increasing vascular permeability and blood flow Many systemic immunologic diseases in humans are caused by the deposition of immune complexes in blood vessels. Systemic lupus erythematosus (SLE) is an autoimmune disease in which complexes consisting of nuclear antigens and antibodies deposit in the kidneys, blood vessels, skin, and other tissues. This also is the mechanism of a disease called post-streptococcal glomerulonephritis that develops in rare cases after streptococcal infection and is caused by complexes of streptococcal antigen and antibodies depositing in the glomeruli of the kidney. In some forms of glomerulonephritis, immune complexes are not detected in the circulation, leading to the postulate that the antigens are first planted in the kidney and the complexes form locally. Group A Streptococci (Streptococcus pyogenes) appear in purulent lesions or broth cultures spherical or ovoid cells in chains of short to medium length (4-10 cells). On blood agar plates, colonies are usually compact, small, and surrounded by a 2 to 3 mm zone of β-hemolysis, which is easily seen and sharply demarcated. β-Hemolysis is caused by either of two hemolysins, streptolysin S and the oxygen- labile streptolysin O, both of which are produced by most group A strains Antigenic Structure Toxin Streptolysin O: Streptococcal Superantigen Toxins: Streptolysin O is a pore-forming Over many decades, these toxins have cytotoxin, lysing leukocytes, tissue been assigned a number of names linked to cells, and platelets. their association with scarlet fever (erythrogenic toxin) and with streptococcal The toxin inserts directly into the cell toxic shock (streptococcal pyrogenic membrane of host cells, forming exotoxins [Spe]). transmembrane pores in a manner StrepSAgs have multiple effects, including similar to complement and fever, rash (scarlet fever), T-cell proliferation, staphylococcal α-toxin. B-lymphocyte suppression, and heightened Streptolysin O is antigenic, and the sensitivity to endotoxin. quantitation of antibodies against it is Most of these actions are due to cytokine release through the superantigen the basis of a standard serologic test mechanism. called antistreptolysin O (ASO). At least one StrepSAg (SpeB) also has direct enzymatic activity digesting tissue and extracellular matrix proteins.  Other Extracellular Products Most strains of GAS The C5a peptidase is an produce a number of enzyme that degrades Streptokinase causes lysis other extracellular complement component of fibrin clots through products including C5a, the main factor that conversion of plasminogen streptokinase, attracts phagocytes to in normal plasma to the hyaluronidase, nucleases, sites of complement protease plasmin and a C5a peptidase. deposition Pharyngitis Group A streptococci are the Transmission is person-to- most common bacterial person from the large droplets cause of pharyngitis in school- produced by infected persons age children 5 to 15 years of during coughing, sneezing, or age. even conversation. This droplet transmission is most efficient at the short Unless the condition is treated, distances (2-5 feet) at which the organisms persist for 1 to 4 social interactions commonly weeks after symptoms have take place in families and disappeared. schools, particularly in fall and winter months.  Poststreptococcal glomerulonephritis It is more common in temperate climates where insect bites lead to impetigo. The average latent period between infection and glomerulonephritis is 10 days from a respiratory infection, but generally about 3 weeks from a skin infection. Nephritogenic strains are limited to a few M types and seem to have declined in recent years.  The renal injury of acute glomerulonephritis is caused by deposition in the glomerulus of antigen–antibody complexes with complement activation and consequent inflammation. The M proteins of some nephritogenic strains have been shown to share antigenic determinants with Pathogenesis glomeruli, which suggests an autoimmune mechanism similar to rheumatic fever. Streptokinase has also been implicated both through molecular mimicry and through its plasminogen activation capacity.   Antigen-antibody complexes are produced during normal immune responses, but they cause disease only when they are produced in excessive amounts, are not efficiently cleared, and become deposited in tissues.  Small complexes are often not phagocytosed and tend to be deposited in vessels more than large complexes, which are usually cleared by phagocytes.  Complexes containing cationic antigens bind avidly to negatively charged components of the basement Pathogenesis membranes of blood vessels and kidney glomeruli.  Such complexes typically produce severe and long- lasting tissue injury.  Capillaries in the renal glomeruli and synovia are sites where plasma is ultrafiltered (to form urine and synovial fluid, respectively) by passing through specialized basement membranes, and these locations are among the most common sites of immune complex deposition.  However, immune complexes may be deposited in small vessels in virtually any tissue.  Deposits of antibody and complement may be detected in the vessels, and if the antigen is known, it is possible to identify antigen molecules in the deposits as well  Immune complexes deposited in vessel walls and tissues activate leukocytes and mast cells to secrete cytokines and vasoactive mediators.  These mediators may cause more immune complex deposition in vessel walls by increasing vascular permeability and blood flow. This also is the mechanism of a disease called post-streptococcal glomerulonephritis that develops in rare cases after streptococcal infection and is caused by complexes of streptococcal antigen and antibodies depositing in the glomeruli of the kidney. In some forms of glomerulonephritis, immune complexes are not detected in the circulation, leading to the postulate that the antigens are first planted in the kidney and the complexes form locally.  Streptococcus pyogenes of M types 1, 2, 4, and 12 were associated Traditionally, APSGN was with epidemic nephritis Nephritogenic considered to be caused resulting from upper by an antigen present in respiratory infections and group A streptococci. M types 47, 49 and 55 were associated with epidemic antigens nephritis following pyoderma. These are the nephritis associated plasmin receptor (NAPlr), identified Presently, two as glyceraldehyde 3- streptococcal antigenic phosphate fractions with substantial dehydrogenase (GAPDH), claims to nephritogenicity and the streptococcal are being actively pyrogenic exotoxin investigated. (erythrotoxin) B (SPEB) and its zymogen precursor (zSPEB) NAPlr is present in early biopsies of APSGN and, since it is not co- localized with complement or IgG, its role as a nephritogen is thought to be related to its plasmin-binding capacity, which facilitates immune complex deposition and inflammation. The nephritogenic potential of plasmin-binding activity has been noted, not only in NALPr but also in SPEB, streptokinase, and enolase. Along with this possibility, patients with APSGN exhibit an increase in urinary plasmin-like activity SPEB, an extracellular cysteine proteinase, is a cationic (pK>8.0) antigen that is co-localized in the glomeruli with complement and Ig deposits, and is the only streptococcal antigen that has been demonstrated within the electron dense subepithelial deposits (humps) that are the hallmark of APSGN  SPEB/zSPEB induces chemotaxis and increases angiotensin II production by mesangial cells.  Recent studies have demonstrated that the Fc portion of antibodies directed to SPEB bind to the C-terminal domain (rSPEB 345-398), and that immunization with this domain prevents group A streptococcal infection in mice.  The attractiveness of a charge-related GBM penetration in the pathogenesis of APSGN to showed that histones enter the circulation after streptococcal lysis and are capable of inducing in situ immune-complex formation.  Both NALPr and SPEB are capable of inducing monocyte chemoattractant protein 1 (MCP1) and IL-6 in mesangial cells and SPEB elicits the release of a variety of cytokines and interleukins from peripheral blood leucocytes  Activation of the complement system is a consequence of the antigen/antibody reactivity found in glomeruli.  The alternate pathway of complement activation is usually activated in APSGN and is manifested by a depression of C3 levels.  However, some patients may also have a reduction in their levels of C1 and C4.  In these patients, there may be a role for Protein H, a surface streptococcal protein that may activate the classic pathway of complement activation, in combination with IgG.  In addition, in some patients, there may also be complement activation by the lectin pathway; but APSGN may develop in individuals who are genetically unable to activate this pathway In addition to humoral immunity, cellular immune mechanisms are also activated in APSGN. It has long been known that there is an overexpression of cellular adhesion molecules (ICAM-1, LFA-1) and infiltration of lymphocyte and macrophages in the glomeruli of these patients. Higher numbers of CD4-positive lymphocytes are present in renal biopsies obtained in the first 3–4 weeks of the disease and decrease afterwards. Increased glomerular expression of IL-8 correlates with neutrophil infiltration and transforming growth factor–β with mesangial expansion  Poststreptococcal glomerulonephritis is primarily a disease of childhood that begins 1 to 4 weeks after streptococcal pharyngitis and 3 to 6 weeks after skin infection. It is characterized clinically by edema, hypertension, hematuria, proteinuria, and decreased serum complement levels. Pathologically, there are diffuse proliferative lesions of the glomeruli. Clinical manifestations The clinical course is usually benign, with spontaneous healing over weeks to months. Occasionally, a progressive course leads to renal failure and death.  Diagnosis Given the importance of the Detection of group A antigen detection of group A These methods are rapid and extracted directly from throat streptococci in the prevention specific, but are at best only swabs is now available in a of ARF (it is the reason 90% sensitive compared with wide variety of kits marketed for physicians culture sore throats), culture. use in physicians’ offices. missing 10% or more of cases is not tolerable. Patients with a positive direct antigen test may be treated Several serologic tests have without culture, but the been developed to aid in the They include the ASO, anti- American Academy of diagnosis of poststreptococcal DNAase B, and some tests that Pediatrics recommends that sequelae by providing combine multiple antigens. negative results must be evidence of a previous GAS confirmed by culture before infection. withholding treatment.  Treatment Concentrations as low as 0.01 Numerous other antimicrobials are Group A streptococci are highly μg/mL have a bactericidal effect, also active, including other β- susceptible to penicillin G, the and penicillin resistance is so far lactams and macrolides, but not antimicrobial of choice. unknown. aminoglycosides. Adequate treatment of Patients allergic to penicillin are streptococcal pharyngitis within 10 usually treated with clindamycin or days of onset prevents rheumatic Treatment of the acute infection azithromycin, and impetigo is often fever by removing the antigenic may not prevent the development treated with clindamycin to cover stimulus; its effect on the duration of acute glomerulonephritis. the prospect of S aureus of the pharyngitis is not dramatic involvement. because of the short course of the natural infection. Prevention  Multivalent vaccines using M protein epitopes that are not cross-reactive to self are in clinical trials with encouraging results. Any questions?