Antigens must be located in the kidney and elicit local immunoinflammatory reactions to cause immune-mediated kidney diseases. Renal antigens are naturally located in the kidney and are components of the kidney's protein composition. Non-renal antigens require certain mechanisms for deposition (implantation) in the kidney.
Renal antigens and some non-renal antigens that circulate and deposit in the kidneys are fixed targets for antibody binding. Typically, non-renal antigens that cause kidney diseases are present in the blood. They form immune complexes by binding to specific antibodies and circulate into the kidneys. Depending on their biological and chemical characteristics, immune complexes have specific localizations in the kidneys: mesangium of glomeruli, glomerular basement membrane (GBM), endothelial cells on the inside of GBM, and epithelial cells on the outside of GBM. For example, in IgA nephropathy (Berger's disease), the immune complex contains IgA, which, due to its larger molecular size, tends to localize in the mesangial area. Combinations of bacterial antigens with IgG, on the other hand, due to their smaller molecular size, tend to localize within the GBM or on the side of GBM epithelial cells.
Once localized, antigens and immune complexes cause and sustain persistent immunoinflammatory renal injury, often through one or more classical immune responses. Less common types include those mediated by IgE, direct complement activation, and immunodeficiency diseases (such as AIDS, congenital deficiency of complement components), with the type of histopathological damage depending on the localization and type of immune response.
1. The pathogenesis of IgE-mediated (type I, immediate or hypersensitivity) kidney diseases is the activation of immune reactions mediated by allergen-sensitive T cells, which, upon contact with specific allergens, release pro-allergenic interleukins IL-4, IL-5. These interleukins promote the production of IgE and activate mast cells and basophils. Mast cells and basophils coated with IgE release vasoactive proteins (such as histamine) and chemotactic factors (such as IL-4) upon exposure to allergens, causing vasoconstriction, prostaglandin synthesis, platelet-mediated coagulation, thrombosis, and fibrin deposition. In several kidney inflammatory diseases, there may be IgE deposition and infiltration of eosinophils. The occurrence of allergic interstitial nephritis caused by the use of penicillin (especially methicillin) is partly attributed to IgE-mediated hypersensitivity. It is accompanied by increased eosinophils, renal eosinophil infiltration, and IgE deposition, and is responsive to corticosteroid therapy, often improving quickly after discontinuation of the causative drug.
2. Cytotoxic antibody-mediated (type II hypersensitivity) kidney disease, anti-glomerular basement membrane disease (Good-pasture's disease) is the prototype of this type of kidney disease. The kidney damage is caused by the linear deposition of specific antibodies against type IV collagen in GBM. Antibodies bind to corresponding antigens to form immune complexes that activate the complement system, a group of plasma and membrane proteins with enzymatic activity, chemotactic properties, binding, and regulatory characteristics. Complement can be activated via C1 (classical pathway) or C3 (alternative pathway), forming a protein called membrane attack complex (MAC), which is composed of complement components C5-9. MAC causes tissue damage, either directly through membrane channels or indirectly by attracting other inflammatory cells to participate in the immune response. For example, complement fragments C5-7 attract neutrophils to the site of inflammation. Neutrophils can release lysosomes, further causing tissue damage, and can directly damage and penetrate GBM. Moreover, reactive oxygen species (i.e., free radicals, superoxides), leukotrienes, and can interact with platelets to activate the coagulation system, stimulate fibrin deposition. Therefore, in anti-glomerular basement membrane disease, cytotoxic antibodies are deposited linearly along GBM, although the complement distribution is relatively irregular and intermittent, it is also approximately linear. The histopathological feature is necrotic destruction of glomerular structure, with fibrin deposition and formation of fibroblastic crescents.
3. Antineutrophil cytoplasmic antibodies (ANCA) can also cause immune kidney disease mediated by cytotoxic antibodies. They play a role in Wegener's glomerulonephritis and other vasculitic kidney diseases. Although there is no deposition of immune components in immunofluorescence examination and it appears as oligoimmune, it is best to classify ANCA-related kidney diseases into the category of immune-mediated kidney diseases because ANCA plays a causative role. Although there are different types of ANCA, each recognizes a specific neutrophil cytoplasmic component (such as myeloperoxidase, lysosome, elastase, protease 3, lactoferrin, cathepsin B, D, G), most plasma containing ANCA is specific for only one antigen. In fact, all C-ANCA are specifically targeted to protease 3, while P-ANCA targets myeloperoxidase. Wegener's granulomatosis is the prototype of ANCA-mediated kidney diseases, and almost all cases of the disease are associated with ANCA.
The initiating factors of ANCA are not yet known, but it is believed that the interaction between ANCA and neutrophil cytoplasmic antigens activates neutrophils. The upregulation of integrins on the cell surface attracts neutrophils and allows them to roll along the endothelial cells of the kidneys or other affected organs in the process of vasculitis. The adhesion of neutrophils to endothelial cells upregulates ligands on the endothelial cell surface, including intracellular adhesion molecule-1 and endothelial-leukocyte adhesion molecule-1. These ligands strengthen the binding between activated neutrophils and endothelial cells, leading to various immune-inflammatory reactions, such as the generation of reactive oxygen species, lysosomal degranulation, T cell activation and release of lymphokines, causing damage to endothelial cells.
4. The vascular endothelial cells of the glomerulus are particularly susceptible to damage. Although there is rarely deposition of immunoglobulins, it has been proposed that the positive charge of protease 3 or the autoantigen of myeloperoxidase allows the ANCA-antigen immune complex to bind along the GBM and endothelium. The implantation of ANCA-antigen immune complexes along the GBM initiates ANCA-mediated kidney injury and amplifies it. The histopathological characteristics of clinical Wegener's granulomatosis are necrotizing rapidly progressive crescentic glomerulonephritis and granuloma formation in the kidney and respiratory tract mediated by T cells.
5. Idiopathic necrotizing glomerulonephritis and rapidly progressive glomerulonephritis (not involving the respiratory tract), microscopic polyarteritis, a common kidney vasculitis, involving small blood vessels in the kidney or other organs, without granuloma or immunoglobulin deposition, and ANCA activation of neutrophils may also be a pathogenic cause.
6. Immune complex-mediated (Type III hypersensitivity) kidney disease, immune complexes are located in the mesangium, glomerular capillary wall, or renal interstitium, and are often found in the circulation. Renal biopsy shows that antibodies and complements are deposited in these areas in a 'mass-like' manner.
7. The basic mechanism may be the same as that of animal model experiments. In animal experiments, exogenous proteins are administered parenterally to stimulate the production of specific antibodies, which bind to antigens to form immune complexes. Antigens are implanted in the kidney or are in the circulation, followed by deposition. The implanted antigens attract antibodies in the circulation to form local immune complexes. Additionally, the increased production of antibodies leads to the formation of circulating immune complexes, and the size of these circulating immune complexes increases, making them more easily cleared from the circulation by reticuloendothelial cells or localized in the mesangium or capillary wall. Since small immune complexes are difficult to deposit, and large complexes are easily cleared by reticuloendothelial organs (such as the liver, spleen, and lymphatic system), this reduces deposition in the kidney. In the formation of immune complexes, various endogenous and exogenous substances can act as antigens. For example, in lupus nephritis, endogenous nuclear proteins can lead to the formation of DNA-anti-DNA immune complexes. In post-streptococcal glomerulonephritis, streptococcal cell wall antigens can form immune complexes.
Increasing evidence shows that the implantation of immune complexes is through many mechanisms, some antigens have specific affinity for GBM. Some of the antigens that are implanted may be altered natural antigens or viruses that have reached the renal tissue through the circulation. In addition to the type and source of antigens, there seem to be many factors that can affect localization, such as the release of vasoactive substances, increased vascular permeability, the size, shape, and antigen-antibody ratio of immune complexes, as well as whether there are receptors that can activate C3b on the glomerular epithelial cells and whether there are receptors for IgGFc segments on mesangial cells and interstitial cells.
Immunocomplexes deposit on the glomerular capillary wall, mainly in the subepithelial region. The localization of immunocomplexes and the activation of complement are the basic pathogenesis of immunocomplex-mediated rapid progressive glomerulonephritis. The activation of complement stimulates various immune phenomena, including attracting neutrophils and releasing lysosomes, and the release of other lymphocytes and cytokines. In fact, all renal pathological types can be observed, including minimal change, mesangial proliferative, membranous, membranous proliferative, mesangiocapillary, necrotic, and rapid progressive glomerulonephritis.
8. Cell-mediated (Type IV or delayed-type hypersensitivity) kidney disease The prototype of this type is renal transplantation. Renal transplantation between monozygotic twins does not induce immune response due to the same graft antigen and host antigen. However, in almost all non-identical twin transplants, the allogeneic antigen of the transplanted kidney triggers an immune response, mainly a cell-mediated immune response. The HLA in the cells of the transplanted kidney is processed by monocytes and macrophages, releasing IL-1 and activating helper T cells. The activated helper T cells, with the participation of IL-2, stimulate other T cells to transform them into cytotoxic T cells, which can attack foreign antigens on the transplanted kidney, causing cell-mediated immune inflammation. If the host is sensitized to the antigen on the transplanted kidney, the transplant can trigger hyperacute rejection, a type of antibody-mediated attack on the renal capillary endothelium, leading to acute renal ischemia, infarction, and loss of the transplanted kidney.
Cell-mediated kidney disease also plays a certain role in the pathogenesis of poststreptococcal glomerulonephritis (PSGN). Lymphocytes sensitized by contact with streptococcal cell wall antigens can cross-react with glomerular antigens, leading to progressive cell death and fibrosis of the renal parenchyma.
9. Complement directly mediates kidney disease. This disease occurs in the absence of antigens or antibodies, with the deposition of C3 and C4b2a in the mesangium and glomerular capillary walls. Immunofluorescence examination often fails to detect early complement components and immunoglobulins. When C4b2a splits C3, with C3 activator, C3 activator converting enzyme, and natural C3 as cofactors, the alternative pathway can be activated. These molecules are normal serum components, and the activation of the alternative pathway is often controlled, so there is no excessive deposition of activated C3. As for how the alternative activation pathway becomes disordered and leads to the precise mechanism of C3 deposition in the kidney is not yet clear. In patients with immune-mediated kidney disease mainly related to C3 deposition, about half of the serum has a protein that can directly cleave C3 to generate activated C3b. This molecular C3 nephritis factor is an IgG autoantibody with a molecular weight of 150,000 that is heat-resistant. C3b can deposit in the glomerular mesangium with phagocytic function, under the endothelium, or along the C3b binding sites on the capillary wall, triggering local immune inflammatory injury.
The characteristic of spinal activation by complement is the proliferation of intracellular components within the renal corpuscles and the thickening of the capillary wall. These changes are called membranous proliferative glomerulonephritis (MPGN) in renal biopsy, which can be divided into type I, II, or III. Type I is mainly the deposition of C3 along the capillary wall in the subendothelial space, type II is mainly dense deposits within the membrane, and type III is a mixture of type I and II.
HIV infection can be accompanied by progressive kidney disease. Intravenous drug use is an important risk factor, but not every patient has a history of intravenous drug use. Acute HIV-related focal segmental glomerulosclerosis with proteinuria is more common in men, urban areas, and black people who use intravenous drugs, while in white people and seropositive homosexuals with no proteinuria, the progression of HIV nephropathy is slower.
The histopathological features are the early appearance of focal segmental glomerulosclerosis and focal deposition of IgM and C3, and later renal biopsy tissue shows more widespread collapse of the entire glomerulus. The renal interstitium is often infiltrated by many CD8+CD2+ T cells. The presence of a reticular structure in glomerular endothelial cells suggests direct attack by viruses or viral particles as antigens implanted in HIV nephropathy, leading to immune-mediated kidney lesions. In addition, kidney involvement in HIV patients with immune complex type may be due to circulating bacteria, viruses, or related tumor immune complexes, which initiate immune complex-mediated kidney lesions. Excessive antibody-mediated immune responses can also cause this type of kidney involvement, as polyclonal hypergammaglobulinemia has been reported in HIV nephropathy infections.
Congenital deficiency of complement components may be due to impaired processing of autoantibodies in the circulation, and these deficiencies are associated with some rare immune-mediated kidney diseases. There have been reports of renal cortex necrosis in patients with H factor deficiency, a SLE-like syndrome, and a hemolytic uremic syndrome. The mechanism is unclear. However, immune system disorder, either excessive or insufficient, may be a predisposing factor.
