First, SLE immune disorder caused by estrogen receptor
In the past 50 years, people have noticed that there are obvious gender differences in the incidence rate, which is related to the age of women. The incidence of women of childbearing age is 10 times that of men, and the incidence of women of non-childbearing age is three times that of men. The above trend can also be seen in mice, and the onset of female mice is earlier and heavier than that of male mice. SLE women who take oral estrogen contraceptives will have the initial clinical symptoms of SLE or make their condition worse (1). According to Junlger's research, male SLE patients have normal testosterone (TG) and elevated estradiol (E2). In female SLE patients, Te is decreased and E2 is normal. However, regardless of the levels of Te and E2 in the blood of male and female patients, the E2 metabolite 16- hydroxyestrone in the blood of negative SLE patients is bound to increase, and 16- hydroxyestrone has estrogen-like activity, which can combine with estrogen receptor (er), suggesting that estrogen is related to the occurrence and development of SLE.
F2 must combine with specific ER to produce biological effects. ER exists not only in gonads, but also in foot glands, lymph nodes, spleen, reticular tissue, central nervous system and bone marrow. In recent years, ER has also been found in OKT8+ cells. The combination of estrogen and estrogen receptor has the following effects, which may be related to SLE immune disorder: ① the combination of estrogen and estrogen receptor in thymus epithelium makes thymus atrophy (2), which reduces thymosin production, thus reducing lymphocyte activity; ② In human or SLE model (BZN/WF 1), Ts activity and IL-2 content decreased after E2 treatment; In patients with Creutzfeldt-Jakob syndrome, before androgen administration, the percentage of 0KT3+ and OKT8+ decreased, and the ratio of okt 4+ to okt 8+ increased. After androgen treatment, OTK3+, OKT8+ and OKT4+/OKT8+ all returned to normal, which was consistent with the remission of patients' symptoms (3-5). ③E2 can promote the differentiation and maturation of B cells, and the hyperfunction of B cells in SLE patients may be caused by estrogen inhibiting ts activity (6); ④E2 can reduce the number of NK cells; ⑤ After E2 binds to er of mononuclear macrophages, it delays the clearance of immune complex (IC) by macrophages, while Te can increase this clearance (7). It has been proved that estrogen, by combining with ER, causes Ts decrease, T 12 and B cells hyperfunction, and the ability of mononuclear macrophages to clear IC decreases, which is one of the causes of SLE.
Second, the relationship between SLE and autoantibodies
SLE patients produce a variety of autoantibodies, which is one of the important foundations of SLE as an autoimmune disease. Such as: anti-nuclear antibody (ANA), anti-cytoplasmic antibody and various anti-cell antibodies, among which state ANA is of great significance in the pathogenesis and diagnosis of SLE, but there are also different views recently. The autoantibodies related to SLE are summarized as follows (8).
1. Anti-ANA: Ana exists in circulation of 90% SLE patients, which is of great significance for exploring the pathogenesis and diagnosis of SLE. However, ANA is not completely specific to SLE (9), and it has some limitations in diagnosing SLE. At present, some antibodies against mononuclear components have been found. There are many evidences that ANA is involved in the formation of immune complex in SLE and plays a role in the pathogenesis of SLE (10). ANA was mostly IgG(87.5%) and IgM (33%).
2. Anti-double stranded DNA antibody (anti-ds-DNA antibody); It is an anti-ANA antibody in SLE patients, also known as anti-nDNA, which is highly specific for the diagnosis of SLE. This antibody can be detected in more than 75% patients with untreated active SLE, and its titer is parallel to the degree of disease activity. After using immunosuppressant, its titer decreased rapidly. In patients with natural remission, the titer of this antibody is very low (1 1). The IC formed by ds-DNA and anti-ds-DNA antibody plays an important role in the pathogenesis of SLE and SLE nephritis, so some people think that detecting this IC is specific for SLE.
3. Anti-single-stranded DNA antibody (anti-ss-DNA antibody): It is another anti-DNA antibody of SLE patients, also called anti-d DNA. The detection rate of anti-ss-DNA antibody in serum of SLE patients is very high, especially in drug-induced SLE. Can appear at the same time with anti-ds-DNA antibody, or not at the same time or only one. Meddison et al. pointed out (12) that 57% of ANA negative patients had anti-ss-DNA antibodies. Because this antibody appears in low titer in other connective tissue diseases and chronic active hepatitis, its specificity for SLE is not as good as that of anti-ds-DNA antibody. However, it has certain value for patients with ANA negative and clinical manifestations consistent with SLE.
The antigens of the above two anti-DNA antibodies are DNA. Studies have proved that DNA molecules in SLE blood are endogenous, which may be due to DNA degradation in lymphocytes and that part of DNA that has not been cleared in time. The DNA with high G+C% group-specific structure in serum of SLE patients is the antigen of anti-DNA antibody. There are many anti-DNA antibodies in patients with systemic lupus erythematosus. After IC is produced, it is found that anti-DNA antibodies have a very important property-cross-reactivity, that is, monoclonal anti-DNA antibodies can react with various components including ss-DNA, z-DNA synthetic polynucleotides, phospholipid polysaccharides, platelets, Raji cells, histones and structures with a large number of negative charges to form anti-DNA antibodies.
4. Anti-nuclear bran eggshell antibody (anti-Sm antibody): It is a non-nucleic acid macromolecular structure, and the specific antigen structure is not clear. It can be detected in 25% SLE patients. It is generally believed that this antibody is also highly specific for SLE. The appearance of anti-Sm antibody alone is related to the damage of central nervous system in SLE, which is easy to involve kidney and Raynaud's syndrome. However, it is difficult to evaluate the significance of having anti-Sm antibodies, because such antibodies often appear together with ds-DNA antibodies and anti-nRNP antibodies (8. 14).
5. Anti-RNA protein antibody (anti-nRNP antibody): Also known as Mo antibody, Sm nuclear nRNA is the main component of soluble nuclear antigen (ENA). NRNP is closely related to Sm antigen. Although they have their own antigenic determinants, their immune response is accompanied by multiple stages. About 40% SLE patients can detect anti-nRNP antibodies. The incidence of renal damage is low when it appears alone, but it can occur when it appears with other antibodies, especially ds- DNA antibodies. The incidence of Raynaud's syndrome and scar discoid lesions increased with anti-nRNP antibody. Anti-nRNP antibody is not specific for SLE, because mixed connective tissue disease and drug-induced SLE have such antibodies.
6. Anti-ADP- ribose antibody [anti-poly (ADP- ribose) antibody]: There is an IC in the blood circulation of ]:SLE patients, which combines poly (ADP- ribose) and anti-poly (ADP- ribose) antibodies. The binding activity of poly (ADP- ribose) is limited to IGF-AB fragment, and the binding activity limit is 20%. More than 20% is only found in SLE and some SLE-like patients. The binding activity of anti-DNA antibody is above 30%, which is not only found in SLE and SLE-like diseases, but also in rheumatoid arthritis and chronic active hepatitis. Therefore, the detection of anti-poly (ADP- ribose) antibody may be more specific than that of anti-DNA antibody (15).
7. Precipitated antibody against cytoplasmic antigen (anti-R0 antibody): KB cells and human peripheral blood leukocytes were used as substrates to purify anti-R0 antibody for immunofluorescence staining. It was found that fluorescein labeled with anti-R0 antibody was stained in cytoplasm, which proved that anti-R0 antibody was an antibody in cytoplasm. The renal eluate of SLE patients who died of anti-R0 antibody positive is rich in anti-R0 activity. It is suggested that IC composed of anti-R0 antibody and corresponding antigen may play a role in the pathogenesis of SLE nephritis. Neonatal SLE is closely related to anti-R0 antibody, which is considered as a marker of the disease. The anti-R0 antibody of newborn may come from a group without any symptoms, but there is anti-R0 antibody in the blood of this mother.
8. Antibodies against nerve tissue components: There are many kinds of IgC and IgM autoantibodies against nerve components in circulation of SLE patients, and there are brain reactive cytotoxic antibodies in cerebrospinal fluid, which are related to the injury of short axis nerves. One is anti-glycolipid antibody. The detection rate of anti-glycolipid sialic acid -GM 1 antibody (IgG type) is very high in SLE patients with nervous system damage. The mechanism of SLE producing anti-Asialo-GM 1 antibody is not clear. It may be that the nerve cells of GM 1 combine with antibodies to activate complement, which leads to the cytotoxicity of brain tissue. The antibody is of great significance in differentiating malignant brain sores. The other is anti-Neuro-2a antibody (anti-Neuro-2a antibody), and its corresponding antigen is on the surface of mouse Neuro-2a cells. The titer of anti-Neuro-2a antibody in patients with brain ulcer is 2-6 times higher than that in patients without brain injury.
9. Anticardiolipin antibody (ACL): ACL antibody can bind to one of IgG, IgM or IgG-IgM complex antibody in phospholipid antigen, which is found in autoimmune diseases such as SLE. The level and positive rate of ACL anti-secondary in SLE patients not only increased significantly, but also the level of ACL antibody (mainly IgG) was positively correlated with the disease activity index of SLE patients. For example, in 10 SLE patients with renal damage, the positive rate of ACL antibody was as high as 85%, and with the improvement of renal damage, ACL antibody also recovered or approached normal level. At present, it is considered that ACL antibody is related to many clinical symptoms of SLE, such as repeated thrombosis, habitual abortion, nervous system symptoms, reticular macula, leg ulcer and so on. Therefore, the syndrome group associated with ACL antibody is called Articardiolipin Syttdrome, and thrombosis is the main feature of this syndrome (16).
Thirdly, the relationship between immune disorder of SLE and the function of T and B lymphocytes.
B cells of SLE patients produce a large number of IgG/IgM antibodies, of which IgG is absolutely dominant. It is suggested that SLE patients have immunomodulatory disorder of immunocompetent cells.
1. Regulatory disorder of immunocompetent cells: Abnormal increase of B lymphocyte reactivity is a significant feature of immunocompetent cells in SLE patients. The reasons for the transitional activation of B cells are as follows: ① Spontaneous activation, that is, in active SLE patients, B cells can spontaneously secrete high levels of anti-DNA antibodies. There are two subgroups of B cells producing anti-DNA antibodies in SLE patients, namely, CDs+B cells, which mainly produce IgM anti-DNA antibodies, and CDs-B cells produce IgG and IgA antibodies (17). ② The number and functional defects of TS cells are reduced, while Th cells are highly responsive to auxiliary signals and low responsive to inhibitory signals. Even in SLE patients, there are abnormal Th cells with CD4-/CDG phenotype, which express α/β TCR. These cells are rare in normal people, but they are abnormally increased in SLE, which can help B cells to produce pathological autoantibodies such as IgG anti-DNA antibodies. ③ Monocytes participate in the regulation of anti-DNA antibody synthesis.
2. The role of mitogen, antigen and mediator; Phytolacca acinosa (PWM) can induce DNA patients to produce IgM anti-DNA antibodies: DNA can specifically stimulate PBMC of active and remission SLE patients to secrete IgG anti-dsDNA antibodies, but it has no obvious effect on normal cells. It is speculated that there are memory cells secreting this antibody in the peripheral blood of SLE patients (18). Recently, it has been reported that interferon-γ, interleukin -2, prostaglandin E2, interleukin -6, etc. It can induce PBMC or B cells of SLE patients to secrete anti-DNA antibodies (19-2 1).
3. Regulation of anti-DNA idiotypic antibodies: About 230 anti-DNA idiotypic antibodies were obtained from human hybridomas by monoclonal antibody technology. Most normal people have anti-ds-DNA idiotypic antibodies in their blood, which show Ab2α activity. It can inhibit the synthesis of anti-DNA antibodies after binding with T and B cell antigens. These antibodies are ubiquitous in SLE patients, and they show Ab2β and/or Ab2γ activity. Promote the production of anti-DNA antibody (18).
4.4 Changes of colony forming ability and T cell subtypes. SLE patients: T lymphocyte colony forming unit (TL-CFU) can reflect the activity level of progenitor cells or precursor cells with the ability of T cell proliferation and differentiation in cellular immune system. This colony-forming cell has the characteristics of cells and is the only cell with self-renewal ability in peripheral blood. Su Yaping found (22, 23) that T lymphocytes in peripheral blood of SLE patients had colony-forming ability, but the number was significantly lower than that of normal control group, and the number of colonies in patients with renal damage was significantly lower than that in patients without renal damage. At the same time, T3+, T4+ and T8+ cells in SLE patients were lower than those in the control group, while T4+/T8+ cells were higher than those in the control group. T cell subsets in active patients were lower than those in inactive patients, in which T8+ decreased most obviously and T4+/T8+ increased significantly. Correlation analysis shows that T3+, T4+ and T8+ are positively correlated with TL-CFU and negatively correlated with T4+/T8+. To determine the correlation between ANA titer and t-leprosy subtype. Results The higher the titer of ANA, the lower the number of T8+ cells, which was negatively correlated with T4+/T8+. It is suggested again that Tg, cell defect and overactivation of B cells (producing too many autoantibodies) are important mechanisms of SLE (24).
Fourthly, the relationship between the damage of tissues and organs in SLE patients and the function of FC receptor and C3b receptor in mononuclear phagocytes.
It has been reported in stomatology that the complement CT inhibitor (CTINH) in the blood of SLE patients is significantly higher than that of normal people, and TCINH is the specific inhibitor of the first phase of complement activation, suggesting that complement activation in SLE patients is impaired. The C4 content of SLE patients was significantly lower than that of normal people (25). SLE not only has low complement quantity, but also has defective complement receptor function, which is an important reason for IC deposition in systemic lupus erythematosus. C3b receptor, that is, type I complement receptor (CR 1), is mainly distributed in red blood cells and mononuclear macrophages, and its biological functions are as follows: ① Red blood cells rapidly transport IC bound to CR 1 to the liver for treatment and release; ② Monocyte phagocytes (MP) or neutrophils (PMN) phagocytize C3b conditioned particles or ingest C3b coated IC; ③ Regulating B cell differentiation and antibody production (26, 27). Using isotope labeling method, the CR 1 number of erythrocytes in SLE patients (2800 241) was significantly lower than that in healthy people (5014155), and the CR 1 number of glomerular podocytes, PMN and B cells in SLE patients was lower than that in normal people. Low CR 1 is mostly acquired, but there are also some genetic factors, because high or low CR 1 on red blood cells has family aggregation. CR 1 deficiency is the most important factor of IC(CIC) clearance in SLE patients.
Under normal circumstances, CIC activates complement, combines with CR 1 of red blood cells, transports it to liver and spleen and is swallowed by MPS. Moreover, complement and CR 1 can prevent IC from "capturing" outside MPS, while the number of CR 1 in SLE patients decreases, resulting in the loss of red blood cells' ability to adhere to CIC, which leads to IC accelerating "capturing" outside MPS and depositing in tissues.
MPS is an important place for normal body to clear IC. In animal experiments, if the phagocytic function of MPS is blocked, the circulating ic will increase and a large number of IC will be deposited in tissues (28). Li Xiaodong and others found that the function of clearing IC mediated by FC-R in SLE patients was significantly lower than that in the control group (SLET1/2233.44172.69, normal 74.58 32.55), and the function of clearing IC by FC-R was significantly related to the level of CIC and anti-ds-DNA antibody in SLE patients. However, the nonspecific clearance function of SLE is basically normal, suggesting that the nonspecific clearance function and receptor-mediated clearance function are different (29).
5. Relationship between systemic lupus erythematosus and interleukin-2 and interleukin-6
Xie Hong Fu et al. found that the level of IL-2 produced by PBMC in SLE patients and inactive patients was significantly lower than that in normal people (SLE 37. 15 14.7, normal 62.438+0.25.97) (30). Zheng Min et al. detected soluble interleukin -2 receptor (sIL-2R) in serum of SLE patients by EliSA double antibody sandwich method, and this antibody in serum is an index (365, 438+0, 32) reflecting the activation state of T lymphocytes in vivo. The results showed that: ① the level of serum sIL-2R in ①SLE patients was obviously abnormal; ② Serum sIL-2R level in ②SLE patients was positively correlated with disease activity and organ damage (32, 34); The expression of IL-2R in peripheral blood lymphocytes of SLE patients induced by PHA was dynamically observed by indirect fluorescence of WuTac monoclonal antibody. It was found that the expression of sIL-2R in SLE lymphocytes was significantly lower than that in the control group (35). Damle et al. confirmed (36) that normally activated Ts cells not only inhibited the proliferation of Th cells, but also inhibited the release of sIL-2R from Th cells. As mentioned above, the number and function of Ts in SLE patients are low, and the ratio of Th/Ts is increased, thus promoting the proliferation and hyperfunction of Th, further synthesizing more IL-2R and releasing it into the blood, resulting in a significant increase of sIL-2R, while the IL-2R left on the cell membrane or expressed is reduced (35).
In recent years, [3H]TdR incorporation of IL-6-dependent cell line B9 was used to detect the level of IL-6 production in PBMC of SLE patients. Results The level of IL-6 activity in active and inactive SLE patients was significantly higher than that in normal control group (37, 38). IL-6 is secreted by monocytes, T cells and B cells. Tanaka pointed out that (39) B cells of SLE patients can spontaneously produce IL- 1, IL-4 and IL-6. One of the important biological functions of IL-6 is to promote the differentiation of B cells and produce immunoglobulin (40). In this way, B cells produce IL-6, which in turn promotes the differentiation of B cells and keeps the function of B cells at a high level.
6. Pathogenesis of Raynaud's syndrome in patients with systemic lupus erythematosus.
The incidence of RP in SLE patients is 18-45%, even in heart, lung and kidney of SLE patients (41). It is of great significance to explore the etiology of SLE. Serum IbG, IgM and ACL antibodies in SLE patients were detected by ELISA. It was found that the positive number of IgG-type ACL antibody in RP patients was significantly higher than that in non-RP patients, and the vasculitis-like injury of skin in IgG-type ACL patients also increased (42), because ACL antibody can bind to phospholipids on vascular endothelial cell membrane, which is the cause of vasculitis. It is also reported that TXB2, a metabolite of TXA2 in serum of SLE patients with RP, is significantly higher than that of those without RP (43), indicating that the cause of vasospasm in SLE patients may be due to the increased synthesis and release of TXA2. Vasculitis can induce the synthesis and release of TXA2, and the increase of TXA2 will cause vasospasm and thrombosis, aggravate the symptoms of vasculitis and form a vicious circle.
summary
SLE is an autoimmune disease that produces a variety of autoantibodies. The direct cause of pathological damage of SLE is the increase of IC production and its removal obstacles and its deposition in tissues. There are many related reasons: ① the combination of estrogen and ER leads to the decrease of Ts, the hyperfunction of Th and B cells, and the decrease of the ability of MPs to clear IC; ② A variety of autoantibodies, especially anti-DNA antibodies, cross-react with a variety of tissue components to form multi-system and organ damage. Anti-ds-DNA antibody is related to renal damage, anti-Sm antibody alone is related to neurological damage, anti-R0 antibody and its IC are also related to renal damage, anti-glycolipid antibody and anti-Neuro-2a antibody are related to cranial nerve damage, and anti-ACL antibody is related to thrombosis and neurological symptoms. ③B and Th cells are overactive, while the number and function of Ts cells are low; ④ The ability of clearing IC mediated by MPSC-R and C3B-R (Cr 1) is impaired, which makes CIC sink into tissues; ⑤ IL-2 produced by PBMC in ⑤SLE patients decreased significantly, IL-2R expression in serum increased significantly, and IL-2R expression in cell membrane decreased. Perhaps the initial cause is the overactivity of Th and B cells. The activity of IL-6 in SLE patients is also high, and IL-6 can enhance the function of B cells. ⑥ RP in ⑥⑥SLE is vasculitis injury mediated by ACL antibody, which further increases TXA2 synthesis and leads to vasospasm and thrombosis.