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| Year : 2000 | Volume
: 11
| Issue : 3 | Page : 295-302 |
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| Advances in the Pathogenesis of Glomerulonephritides |
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E Nigel Wardle
21 Common Road, North Leigh, Oxford 0X8 6RD England, United Kingdom
Click here for correspondence address and email
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How to cite this article:
Wardle E N. Advances in the Pathogenesis of Glomerulonephritides. Saudi J Kidney Dis Transpl 2000;11:295-302 |
Advances in the understanding of the pathogenesis of glomerulonephritides are now linked closely with advances in immunology and cell biology, as they apply to the mechanisms of glomerular inflammation. Understandably, the pharmacology of inflammation is involved too. Logically, one should proceed from a consideration of the immune defences, as in [Table - 1].
Therefore, if there is streptococcal tonsillitis the body will use its phagocytes locally in the pharynx to ingest and kill the invading bacteria. Their action will be supported by cell mediated immunity (CMI) involving natural killer lymphocytes (NK) and cytotoxic CD8 T cells (CTLS). If the bacteria spread by the blood stream and locally in the tonsils, activation of the complement system will support the killing process, and at the same time its products will promote inflammation. After a few days, specific antibodies will form to aid opsonization of the invading streptococci. Often the combination of bacterial or viral antigen with specific antibodies in the blood stream will give rise to immune-complexes in the circulating blood. Those that lodge in the renal glomeruli will cause glomerulonephritis (GN). Phagocytic cells (MPS) will clear others as blood goes through the liver and the spleen. Accordingly, a discussion of mechanisms involved in GN will mean focussing on the processes listed in [Table - 2]. Fortunately, there are recent clinically orientated reviews of this subject. [1],[2]
Particularly important advances have appeared in relation to IgA nephropathy (IgAN); the most frequent GN in the world. IgAN patients often have "syn-pharyngitic hematuria", which means that they show exacerbations of hematuria at the time of upper respiratory tract infection or bronchiolitis. For years, there has been focus on viruses, without much evidence for their effect. However, a Japanese group has shown how hemophilus para-influenza bacteria were isolated from the pharynx of their patients, and IgAN patients have elevated IgA antibodies. [3] As for the IgA nephropathy we have always suspected immune complexes containing IgA, [4] which is produced by the respiratory or pharynx mucosa. Recently, IgG antibodies have been shown to be formed against galactose deficient IgA1 molecules that behave as antigens in the circulation of such patients. [5],[6]
Helper T lymphocytes (Th-1 and Th-2)
By 1986, Mosmann had shown that in rodents there are distinct subsets of CD4 T helper lymphocytes. A precursor cell gives rise to Th-0 lymphocytes that secrete a broad spectrum of cytokines, and from these may arise Th-1 cells that secrete interleukin (IL)-2 and interferon gamma (IFN-γ), or Th-2 cells that secrete IL-4, IL5, IL-10 and IL-13. These subsets, that can be found in man too, are suited to the different immunopathological responses, [7],[8] as shown in [Table - 3].
There are some basic rules about these T helper subsets. IFNγ directs formation of Th-1 cells, and IL-4 directs formation of Th-2 cells. [9] IFNγ inhibits Th-2 cells development, whilst often IL-4 inhibits Th1 cell development. Thus they are crossinhibitory. [10] However, in the course of inflammation, cytokines IFNγ + IL-4 can be synergistic, e.g. in promotion of macrophage activity. Virus induced IFN-alpha will costimulate Th-1 cells and macrophage delayed hypersensitivity responses. [11] Since IL-12 leads to IFNγ generation, it then reinforces the response, and there is also help from IL-18; IFNy inducing factor. [12] IL-12 and IL-18 might be called «alarm cytokines» that bring white cells to sites of bacterial or viral invasion. One notes that Th-1/Th-2 cells have distinct chemokine receptors. [13] CCR5 receptors on Th-1 cells means that they are attracted to chemokines MIL-la and MIP-1βγ. Conversely Th-2 cells express CCR3 and so they are attracted towards exotoxin or in response to monocyte chemotactic protein (MCP-1). There is a third cell, which releases the tissue growth factor (TGF) beta; a cytokine that can modulate immune responses. [14]
Th-1and Th-2 cells in glomerulonephritides
Membranous nephropathy is characterized by subepithelial immune complex deposits that can be idiopathic, related to cancer, caused by hepatitis B virus or can be a part of the spectrum of lupus nephritis. The affinity and size of the immune complexes is relevant to subepithelial localization, but so is the fact that the systemic immune response is characterized by IgG4. [15] This means that the initiating antigens evoke a Th-2 type humoral immune response, [Table - 3]. One will note too that IgG4 does not interact with FC receptors on macrophages (to follow). Hence, local inflammation is reduced. Minimal changes nephropathy is not understood but serum IgE values are usually high and IL-13 is secreted in relapses. [16] Thus, it looks like a typical Th-2 cell response, and that would go with its association with T cell disorders as described by Shaloub [17] and with its frequent associations with allergies. In Saudi Arabia allergy to cow, goat or camel's milk in infants might be relevant. [18] Occasionally, the patient also has asthma. A search for IL4 receptor polymorphism as in asthma has been negative. [19] Yet, one will note that IL13 can interact with IL-4 receptors. [20]
Proliferative/crescentic forms of GN are associated with the deposition of IgG1 and IgG3 antibodies, as part of immune complexes, in the glomeruli. This is the case in IgA nephropathy [21] and in membranoproliferative GN (MPGN). [22] MPGN can be a part of a post-infectious nephritis, e.g. pneumococcal antigen after lobar pneumonia and is also commonly seen with hepatitis C virus infection. [23] Yet, C virus is not associated with a "nephritic factor". MPGN looks like a Th-1 delayed hypersensitivity reaction, as do other forms of GN in which crescents occur.
Goodpasture's anti-GBM antibody nephritis
The antibodies that react with the glomerular basement membrane in antiglomerular basement membrane (antiGBM) disease are from subclasses IgG1 and IgG3. This suggests a Th-1 cell induced response. Indeed there are T cells that are specifically reactive with nephritogenic epitopes of the GBM. [24] Such epitopes might become exposed to the immune system when there has been exposure to pulmonary toxins like hydrocarbons or crack cocaine, or as a result of virus infections such as influenza.
Crescentic Nephritis
Th-1 cell mediated delayed hypersensitivity (DTH) reaction in the glomeruli will result in crescent formation. Administering IL-12 ensures such a response. [25] It is well established that crescents develop as proliferating parietal Bowman's capsule epithelial cells along with macrophages, when glomerular damage is so severe as to cause breaks in the glomerular basement membranes. Thrombin and fibrin play a part in this process. One will ask what attracts the monocyte-macrophages? and the answer must be one or more of the chemokines. Local chemokine expression is a prerequisite for infiltration of leucocytes at inflammatory sites. [26] The subject of chemotactic factors and renal inflammation [27] has been reviewed and I need not go into details. MCP-1 is produced by renal mesangial cells, epithelial cells, proximal tubules and interstitial fibroblasts, and attracts monocytes that turn into macrophages. Monocyte influx always follows neutrophils, which are attracted into glomeruli by agents like C5a complement component, IL-8, [28] and MIP-2. The phagocytic cells release powerful enzymes like elastase and produce reactive oxygen species (ROS), [29] which all result in glomerular damage and proteinuria.
How leucocytes express adhesion molecules and interact with other adhesion molecules on endothelium to enhance them to transmigrate into tissues has received much consideration. [30],[31] A recent study [32] on adhesion molecules in chronic serum sickness in rats showed how CDI ib/c is expressed by polymorphonuclear cells (PMNs) and monocytes so allowing interaction with the intercellular adhesion molecules (ICAM-1) on the vascular endothelium. The ICAM-1 expression is increased in proportion to the immune complex deposition, which is related to monocyte infiltration and the degree of proteinuria. Meager [33] has reviewed the contribution of cytokines to the expression adhesion molecules.
Immunologists emphasize how CD40 ligand (L) on T cells can react with CD40 on monocytes, or antigen presenting cells or even on renal tubules to enhance autoimmune reactions. CD40 Ligand transgenic mice show enhanced T cell dependent B cell responses and so produce more antibody. [34] Yet T suppressor cells do normally control this form of enhanced reactivity. [35] CD40 Ligand activated monocyte-macrophages do stimulate mesangial cells so that there is amplification of glomerular inflammation. [36] In fact the benefits of CD4OL blockage have been demonstrated in lupus nephritis. [37]
Another process that serves to enhance glomerular damage is intravascular coagulation. Its association with crescentic nephritis has been known since the 1970s. Expression of Th-1 lymphocytes is accompanied by display of tissue factor thromboplastin on adjacent endothelial cells. Recently, attention has been drawn to thrombin receptors, now renamed protease activated receptors (PAR-1). [38] In nephritis, these receptors are detected everywhere. Thrombin is chemotactic for monocytes. Thrombin can activate T lymphocytes. Generally, thrombin is a mitogen for mesangial cells, which leads to the expression of growth factors like plateletderived growth factor (PDGF). An antagonist for thrombin receptors will soon be available.
The importance of FC receptors in GN
FC receptors for the heavy chains of IgG are important for the handling of immune complexes by phagocytic cells, and their action leads to an intensification of inflammation in the glomeruli. In 1996, Sylvestre et al [39] showed that IgG induced inflammatory responses occur in complement deficient mice. Then Clynes et al [40] in 1998 showed that mice, whose phagocytic cells could not signal through Fc receptors, could only develop mild nephritis in spite of the deposition of immune complexes, as well as the activation of the complement system. Human mesangial cells express Fcy RIII receptors[41] that bind IgG1 and IgG3 (as in a Th-1 response) but they do not bind IgG2. Details of Fc receptors appear in various review articles.[42],][43]
Attempts have been made to characterize any dysfunction of Fc-alpha receptors of IgA on peripheral blood phagocytic and mesangial cells in subjects with IgAN. When IgA or IgG complexes bind to macrophages, their synthesis of complement C3 is increased. [44] When IgA interacts with Fc-alpha receptors of mesangial cells, they promote the expression of tissue factor and via NF-kB activation release of chemokines IL-8 and MCP-1. [45]
Lupus Nephritis
Systemic lupus nephritis (SLE) covers a spectrum of disease from proliferative and crescentic forms of GN to rarer cases of membranous nephropathy. In lupus mice, IgG3 monoclonal antibodies have been demonstrated to induce wire-loop fibrinoid lesion in the glomeruli. In cases with membranous nephropathy IgG4 is deposited as in a Th-2 response.[46]
The essential antigens of lupus are from nucleosomes of damaged cell nuclei, and thus anti-DNA and anti-histone antibodies give rise to the formation of immune complexes. Studies of cytokine production in experimental SLE show that there is an early Th-1 lymphocyte response causing DTH reactions with much tissue damage. [47] This seems to be an accompaniment of a hyper-response IFNy gene.[48] This phase will be followed by a Th-2 lymphocyte response, which limits tissue damage. [49] In animals, there is initially a high output of TNFα, and IL-12 is elevated. Within 2-4 weeks, there is a peak of IL-2 and high IFNγ (as in Th-2). The IL-10 production by B cells is dependent upon IL-10 secretion.[50] Since patients are heterogenous, and one finds them at differing phases of their illness, cytokine profiles are more complex.
SLE exacerbations are certainly accompanied by high levels of IL-12 and IFNγ.[51] Otherwise, there is high IL-10 secretion by monocytes and lymphocytes that should suppress IFNγ output.[52]
Underlying Mediators
I have sought to stress the contribution of immunology in our understanding of GN. However, study of other mediators that play an important role in disease progression come under the aegis of biochemical pharmacology. Consider the important role of angiotensin II in deciding renal injury,[53],[54] and since angiotensin I1 releases[55] TGFβ, in promoting glomerular and tubulointerstitial fibrosis. Furthermore, thromboxane [56] A2, leukotrienes[57],[58] B4 and C4/D4/E4 and platelet activating factor (PAF)[59] all sustain reactions in which white cells become aggressive. Even in minimal change nephropathy, the urinary output of thromboxane, leukotrienes and PAF is increased.
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Correspondence Address:
E Nigel Wardle
21 Common Road, North Leigh, Oxford 0X8 6RD England
United Kingdom
PMID: 18209321
[Table - 1], [Table - 2], [Table - 3] |
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