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Research Progress on Correlation between HLA and SLE Pathogenesis

01/08/2020

Systemic lupus erythematosus (SLE) is an inflammatory connective tissue dermatosis mediated by autoimmunity. It is characterized by the production of a variety of autoantibodies. The study of the pathogenesis of SLE mainly involves genetic, immune and environmental factors. The human leukocyte anti-gen (HLA) system is currently the most complex polymorphic system known to the human body. Since the first HLA antigen was discovered in 1958 (Jean Dausset), studies have shown that HLA is involved in many genetic and immune diseases. The HLA gene belongs to the human major histocompatibility complex (MHC) gene cluster and is located on the long arm of chromosome 6 (6q21). HLA class I genes include HLA-A, B, C, G, etc .; HLA class II genes are located in the HLA-D region (including DP, DQ, DR, DN, DO 5 subregions). The current research on the pathogenesis of HLA and SLE is mainly focused on the HLA-Ⅰ and HLA-Ⅱ regions.

1. HLAⅠ genes

HLAⅠ genes include two types of classical HLAⅠ and non-classical HLAⅠ. Non-classical HLA I class is also called HLA Ib, including HLA-E, F, G, etc. The study found that the HLA-G 3’UTR region is a susceptible factor for SLE in the Philippines and Japan, and is involved in the occurrence of the disease independently of HLA-DRB1. Among them, HLA-G 14bp I / D is particularly closely related to female patients who have had onset in Japan earlier than 20 years old or who had given birth before 20 years old. This may be related to the fact that HLA-G molecules are mainly distributed in the outer chorionic trophoblast cells of the placenta and play an important role in the placental barrier and maternal-fetal tolerance. In addition, Consiglio et al reported that the incidence of HLA-G + 3142G / C polymorphism in SLE patients in Europe, South America and other regions was significantly higher than that of the control group, and the detection of the level of the risk allele HLA-F in vivo may be helpful in determining Stages, efficacy and prognosis of SLE patients in the two places.

2. HLA class II genes

HLA class II genes mainly include HLA-DR, DQ, DP and other subtypes. HLA-DRB1 is particularly closely related to the pathogenesis of SLE, and has been widely studied worldwide. It was recently discovered that HLA-DQA1 * 03:02 is a susceptibility factor for SLE patients in Xinjiang Uygur, which is located in the same genetic locus as DQA1 * 01:01 in European patients, and may have some European Caucasian characteristics with Uighurs in Xinjiang related. HLA-DRB * 09: 01 and * 15: 01 are related to the susceptibility of Japanese SLE patients, and Polish patients have similar genetic background to Japanese. HLA-DRB * 15: 02 is the most significant genetic factor associated with SLE patients in the Philippines. The incidence of Korean patients is mostly related to HLA-DRB * 08, * 09 and * 15: 01. Fine localization studies found that the most significant association with Korean patients was at amino acid position 13 on HLA-DRB1, followed by positions 11 and 26. The amino acid 11-13-26 haplotype supports most of the classical HLA-DRB1 alleles of previously reported Asian and European populations. At present, in HLA-related studies of diseases, it has been found that amino acid positions may confer a greater risk of disease than classical sites. A large number of studies have shown that HLA class II genes are closely related to clinical manifestations and laboratory indicators of patients with SLE, such as age, pregnancy, autoimmune antibodies, and organ damage.

2.1 Age

The age of onset of SLE patients is mostly between 15 and 40 years. In Japan, HLA-DRB * 09: 01 and * 15: 01 often function as complexes, and are the main pathogenic factor for patients with early-onset (age <20 years), while DR17 is in the United States for late-onset (age> 50 years old).

2.2 Gender and pregnancy

80% -90% of SLE patients are women, which suggests that abnormal estrogen levels that change with menstrual period, pregnancy, etc. are the predisposing factors for the onset and exacerbation of SLE in women, which may provide the basis for genetic basis and infection. About 15.8% of SLE patients have miscarriages during pregnancy, 12.5% to 25.5% have preterm births, 19.5% have stillbirths, and about 31.3% fetuses have stunted growth. A recent study found that when a fetus carries HLA-DRB1 * 04: 01, if the mother carries both 0301, 0801, and 1501, the mother’s risk of developing SLE is twice as high as that of women of childbearing age who do not carry these susceptible sites. Analysis of women’s blood circulation during pregnancy exposed to a large amount of fetal material may induce immune abnormalities and cause the occurrence or exacerbation of SLE. Anti-citrullinated protein antibodies (ACPAs) are one of the most iconic autoantibodies in RA diagnosis. HLA-DRB1 * 04: 01 is a genetic factor of ACPAs epitopes, which promotes the exacerbation of the disease by regulating the protein correlation of the EBV virus. Analysis of HLA-DRB1 * 04: 01 and the above-mentioned loci form haplotypes and other forms of immune factors involved in the pathogenesis.

2.3 Antiphospholipidsyndrome,APS

Secondary APS is most severe in SLE. Antiphospho-lipid antibody (aPL) positive appears in about 30% -50% of SLE patients, causing the body to increase prothrombin, activate complement and participate in the formation of defects Sexual placenta, etc., lead to symptoms such as thrombosis, habitual abortion and thrombocytopenia. It is reported that aPL-positive patients have a 6-fold increase in the birth rate of low birth weight infants and a 10-fold increase in the perinatal loss rate after pregnancy. Therefore, it is important to monitor aPL levels in SLE women before pregnancy. SLE patients are prone to a higher cardiovascular risk and a risk of venous thrombosis. Studies have shown that DRB * 04 (DR4) and DRB * 13 (DR6) are related to the SLE-positive antiphospholipid antibody phenotype and vascular events, which mainly cause patients with severe ischemic cerebrovascular disease and venous thrombosis by increasing vascular fragility. In addition, HLA-DRB1 * 07 (DR7), DRw53, DQA1 * 0102, DQA1 * 0201, DQA1 * 0301, DQB1 * 0302 (DQ8), etc. are also closely related to APS. Recent studies have found that 83.3% of APS patients carry b2GPI / HLAII autoantibodies, including patients with antiphospholipid antibody levels in the normal range. The b2GPI / HLAⅡ complex was found in the placental tissue of APS patients, but not in the normal population. Therefore, in APS patients, b2GPI / HLAⅡ is a more important and reliable substance than anti-phospholipid antibody complexes, and it is expected to become a detection indicator to assist in the diagnosis and judgment of disease activity in the future.

2.4 Anti-Sm, ds DNA and snRNP antibodies

Anti-Sm and ds DNA antibodies are the signature antibodies of SLE, and they are very valuable indicators in SLE diagnostic criteria. Sm antibody-positive patients in Japan and South Korea are mostly related to DRB1 * 0701 and * 0901, and DRB1 * 09 or more are involved in the production of anti-Sm antibodies in circulating blood in the form of a complex with 1501. Most studies suggest that autoantibodies in SLE patients are generated by T cell epitopes corresponding to autoantigens and susceptible HLA-D alleles, and the HLA-DR3 region is the main allele that interacts with the environment to produce anti-snRNP antibodies And the production of anti-ds DNA antibodies provides some significance.

2.5 Anti-SSA / SSB antibody positive

The autoantibodies in SLE patients are mainly ANA, anti-ds DNA, antiphospholipid antibodies, and anti-ENA antibodies. In addition to Sm, anti-ENA antibodies include RNP, SSA / Ro, SSB / La, etc. The human antigen-associated transporter 2 gene TAP2 is located between HLA-DM and DO, and its encoded product TAP2 * Bky2 is essential for transferring antigens to MHC I. TAP2 * Bky2 is significantly associated with SS-B / La and SS-A / Ro in patients with Sjogren’s syndrome and SLE, and it is significantly higher in SLE patients with oral ulcers than in the control group. However, HLADRB1 * 08032 and TAP2 * Bky2 have a significant linkage disequilibrium, so it is inferred that HLADRB1 * 08032 is the genetic basis of SLE and SS patients. DRB * 0301 and DPB1 * 0501 are more closely related to anti-SSA / SSB positive in Japanese SLE patients. DPB1 * 05: 01 is also the only one found to be related to La / SSB or Ro / SSA antibodies of Japanese SLE and RA Allele.

2.6 Organ damage

Lupus nephropathy is a very serious complication in patients with SLE, mainly due to the immune response mediated by autoantibodies and renal vascular stenosis and insufficient blood supply caused by arteriovenous thrombosis caused by APS. MHC Ⅱ-mediated activation of T and B lymphocytes is a key factor in the autoimmune response of SLE and lupus nephritis. During the assembly of MHC Ⅱ and antigen peptides, protease S can drive the activation of T and B cells mediated by MHC Ⅱ, thus promoting the occurrence of SLE. US researchers have studied LN mouse models and found that cathepsin S antagonists can specifically reverse these effects and significantly inhibit the progression of lupus nephritis. Patients with SLE often show involvement of multiple organs and systems. Genotyping studies revealed two new phenotype-specific correlation sites. SNP rs5754217 (UBE2L3) was associated with skin involvement, and rs3093030 (ICAM1-ICAM4-ICAM5) was associated with blood abnormalities.

3. C4 allele

The correlation between C4 and SLE was discovered as early as around 1970. The C4 complex is located in the MHC Ⅲ region and presents CNV. There are two homologous genes, C4A and C4B. Genetic mutations result in alleles that are not expressed (null mutations), namely C4AQ0 and C4BQ0. The encoded C4 complement complex is necessary for the activation of the classical complement pathway and the mannose lectin pathway, and plays an important role in the innate and adaptive immune response. There is a strong linkage disequilibrium between C4A and DR3. Haplotypes HLA-A1, B8, Bf * C2 * C, C4A * QO, C4B * 1, and DR3 are the most frequent haplotypes in SLE patients. A * 01-B * 08- (C4A * Q0) -C4B1-DRB1 * 03: 01 (B8) haplotype is the most common haplotype of DRB1 * 03: 01 in the Nordic population. Further research found that there is a certain correlation between C4A * Q0 and DRB1 * 0301. C4A null alleles or gene deletions are associated with Caucasian / African American, Korean, Japanese, and Chinese SLE patients. C4 complete or homozygous deletion is one of the most significant susceptibility factors for SLE. In some samples, 80% of patients showed lupus-like skin lesions. Despite the strong linkage disequilibrium between HLAⅢ and HLAⅡ genes, in recent years, many teams at home and abroad have used linkage analysis and imputation methods to find that HLAⅡ alleles are closely related to SLE in multiple ethnic groups. At the same time, no HLAⅢ region susceptibility has been found Gene or haploid, we can try to study the possible mechanism of HLAⅢ in the future in Chinese Han SLE patients.

4. Conclusion

HLA is the most complex antigen system in humans. The correlation between HLA-DRB * 1501 and disease is particularly complicated in patients with SLE. In Japanese patients, the combination of HLA-DRB * 1501 and HLA-DRB * 0901 is a susceptible factor, while the combination with HLA-DRB * 13:02 and * 14: 03 is the first protection to be found with Japanese SLE Sexual site. Therefore, HLA shows polymorphism and complexity in the pathogenesis of SLE. HLA sites may mostly participate in the occurrence of diseases such as forming a haploid in a chained manner with multiple other sites, suggesting that research on diseases and HLA is being done. Do not analyze the relationship between a single site and the disease at one time. The overall grasp may have unexpected results.

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