summary of research on hla and disease and treatment-九游会ag

[original]
hla (human leucocyte antigen, hla): a human leukocyte antigen, a highly polymorphic complex expressed by a series of tightly linked gene loci. hla is an “identity card” for human biology that recognizes self and non-self and excludes me through immune responses, thereby maintaining individual integrity. the differences in susceptibility of different individuals to disease are largely determined by genetic factors. the current reported hla and disease and treatment relevance are summarized as follows:

hla and autoimmune diseases
1. rheumatoid arthritis: ☆☆☆
hla-dqb1*02, dqb1*06, dpb1*0101, *0402, and *0501 are negatively associated with rheumatoid arthritis, and dqb1*04, dpb1*0401, and *0601 are associated with a high risk of rheumatoid arthritis [1] [2] .
2. type i diabetes: ☆☆☆
hla-dqa1*0103, dqa1*0201, dqa1*0401, dqb1*0301, dqb1*0402, dqb1*0501, dqb1*0503, dqb1*0601, dqb1*0602, drb1*07, drb1*08, drb1*12, drb1*13, drb1*14, drb1*16, drb1*0406 are negatively correlated with type i diabetes, carrying dqa1*0301, dqa1*0501, dqb1*0201, dqb1*0302, drb1*04, drb1*0301, drb1 *0901 the risk of developing type 1 diabetes is high [3].
3. actinic prurigo: ☆☆☆
carrying drb1*03:01 has a high risk of actinic pruritus, or=3.89 [4].
4. addison’s disease: ☆☆☆
carrying drb1*03:01 and drb1*04:04 is associated with a high risk of addison’s disease, and the risk of heterozygous combination is higher, or=22.13 [5].
5. ankylosing spondylitis: ☆☆☆☆☆
carrying hla-b27, especially hla-b27*02 and hla-b27*04, is a risk factor for ankylosing spondylitis [6].
6. behcet’s disease: ☆☆☆☆☆
carrying hla-b51 is a risk factor for behcet’s syndrome, or=9.27 [7].
7. celiac disease: ☆☆☆☆☆
carrying hla hla-dq2 and hla-dq8 is a risk factor for behcet’s syndrome [8]. hla-dq2 and hla-dq8 tests are commonly used to exclude celiac disease and should be performed before the diagnosis of celiac disease, such as celiac-specific antibody negative or small intestinal proximal biopsy specimens with mild infiltration changes. for clinically highly suspected celiac disease, there is a specific celiac antibody, and the guidelines recommend hla-dq2 and hla-dq8 analysis to enhance the diagnosis. for asymptomatic individuals, hla testing can also be performed to determine if a celiac specific antibody test is needed. hla typing can also be used to predict celiac disease patients who are not sensitive to gluten-free diets.
8. ulcerative colitis: ☆ ☆ ☆
hla-drb1*08 was negatively correlated with ulcerative colitis, or=0.12, and hla-drb1*13 was a risk factor for ulcerative colitis, or=4.32 [9].
9. juvenile idiopathic arthritis: ☆☆☆
hla-drb1*12 was negatively correlated with juvenile idiopathic arthritis, or=0.55, and hla-drb1*08 was a risk factor for juvenile idiopathic arthritis, or=2.26 [10].
10. multiple sclerosis: ☆☆☆
carrying hla-drb1*1501 is a risk factor for multiple sclerosis, or=3.06 [11].
11. myasthenia gravis: ☆☆☆
hla dqb*03 is inversely associated with myasthenia gravis, carrying hla dqb1*05, drb1*14 and drb1*16 are risk factors for myasthenia gravis [12].
12. narcolepsy: ☆☆☆☆☆
the vast majority of narcolepsy were positive for hla-dqb1*06:02, and 202 chinese southern narcolepsy patients were positive for hla-dqb1*06:02 [13].
13. psoriasis vulgaris: ☆☆☆
hla-dqa1*0501 was negatively correlated with psoriasis, carrying hla-dqa1*0104 (or = 2.33), and dqa1*0201 (or = 3.36) was a risk factor for psoriasis [14].
14. systemic lupus erythematosus: ☆☆☆
hla-dr4, dr11 and dr14 are negatively associated with systemic lupus erythematosus, and hla-dr3, dr9, and dr15 are risk factors for systemic lupus erythematosus [15].
15. uveitis: ☆☆☆☆☆
hla-b27 positive anterior uveitis is the most common type of anterior uveitis, accounting for about 40%-70%, more common in men, alternating monocular or binocular [16].
16. birdshot retinochoroidopathy: ☆☆☆☆☆
about 96% of patients with gunshot-like retinal choroidal lesions carry hla-a29, but many of them carry hla-a29 and do not develop this disease. clinically, hla-a29 gene is used for the diagnosis of shotgun-like retinal choroidal lesions [17].

hla and adverse drug reactions
1. carbamazepine: ☆☆☆☆☆
carbamazepine is a commonly used first-line anti-epileptic drug in the clinic, and is widely used in the neurological and psychiatric fields. its main adverse reactions are manifested on the skin. the cpic guidelines state that carbamazepine is required to detect hla-b*15:02 and hla-a*31:01 sites to guide clinical use of carbamazepine to avoid adverse drug reactions [18].
2. abacavir: ☆☆☆☆☆
abacavir is a nucleoside reverse transcription enzyme inhibitor that reduces viral load in aids patients, with approximately hypersensitivity (hsr) in approximately 4.3% of patients. the cpic guidelines stipulate that abacavir should be tested for hla-b*5701, and abacavir should be avoided when carrying this site to avoid adverse drug reactions [19].
3. allopurinol: ☆☆☆☆☆
allopurinol is an enzyme inhibitor widely used in the treatment of diseases such as hyperuricemia. the common adverse reaction is rash, the incidence rate is about 10%, more common with severe drug eruptions. the cpic guidelines stipulate that hla-b*5801 should be tested for allopurinol. carrying this site should avoid taking allopurinol and avoid adverse drug reactions [20].
4. phenytoin: ☆☆☆☆☆
phenytoin is an antiepileptic drug. the common side effects are rash, mostly rash-like erythema, polymorphic erythema, and stevens-johnson syndrome/toxic epidermal necrolysis. the cpic guidelines state that phenytoin should be tested for hla-b*1502. carrying this site should avoid taking phenytoin to avoid adverse drug reactions [20]. in addition, for patients not carrying hla-b*1502 genotype, cyp2c9 genotype is required. detection [21].
5. lamotrigine: ☆☆☆
lamotrigine is mainly used for anti-epileptic treatment. it is used for simple partial seizures, complicated partial seizures, secondary generalized direct seizures, primary generalized tonic seizures, and can also be used for the treatment of intractable epilepsy. syndrome. the risk of stevens-johnson syndrome/toxic epidermal necrolysis (sjs/ten) is high in patients taking hla-b*38:01 alleles with lamotrigine [22].

hla and car-t
car-t cell therapy belongs to adoptive t cell therapy, which uses antibody variable regions targeting tumor antigens to integrate with t cell receptor constant regions, so car-t cells can recognize specificity in a non-mhc-restricted manner. tumor antigens simultaneously activate killer t cells and play a role in killing tumor cells. depending on the source of t cells, car-t cell therapy can be divided into patient (autologous) sources and donor-derived (allogeneic) car-t cell therapy.
1.hla and allogeneic car-t treatment: ☆☆☆☆☆
at present, most of car-t is autologous t cells, and patients’ t cells are generally treated with chemotherapy drugs, which are rare and lacking in persistence. in order to overcome this limitation, the use of donor-derived t cells is also an option, which has the advantage of combining the g-effect of car-t killing tumor cells and donors, which is easy to collect and has good persistence; but the donor-derived car-t it also faces the same problems as hematopoietic stem cell transplantation, requiring hla matching, selecting hla-type donors as much as possible, and reducing gvhd and post-transplant rejection [23].
2.hla-a*02:01 and tcr-t: ☆☆☆☆☆
tcr is a specific receptor on the surface of t cells, which binds to cd3 to form a tcr-cd3 complex, which activates t cells by recognizing and binding to antigens presented by mhc, and promotes the division and differentiation of t cells. the mechanism of action of tcr-t is to introduce new genes into common t cells, so that the modified t cells can express tcr which effectively recognizes tumor cells, thereby guiding t cells to kill tumor cells, and tcr-t cells are treated in solid tumors. better than car-t.
in march 2019, guangdong xiangxue precision medical technology co., ltd. (hereinafter referred to as “xinxue precision”), a subsidiary of guangzhou xiangxue pharmaceutical co., ltd., received the “clinical trial notice” issued by the state drug administration, and xiangxue accurately directed to the national drug administration. the application for clinical registration of taest16001 injection new drug submitted by the administration has obtained the first clinical trial license in china. taest16001 injection is the first product of xiangxue’s precision research and development pipeline. taest16001 targets a complex composed of hla-a*02:01 and ny-eso-1 antigen peptides, using lentiviral transduction without self-replication ability. autologous t cells express the tcr specific for ny-eso-1 antigen. clinical pi studies have shown that patients treated with taest16001 can maintain long-lasting t cells in the body and demonstrate better therapeutic effects. clinical patient enrollment requires hla typing to screen patients with hla-a*02:01 alleles.
currently completed or ongoing tcr-t studies and trials are mainly aimed at hla-a*02:01, and jin by et al. found in mice models that t cells against hpv-16 e7-specific antigens are small for hpv tumors. the mouse has therapeutic potential and is ready for clinical research (nct02858310) [24]. an in vitro study by kang s et al found that tcr-cat (tcr-cytotoxic activated t cells) targeting ny-eso-1157-165 hla-a*02:01 specific antigen has good ability to kill tumor cells [25]. in addition, tcr for wt1 and hla-a*24:02 target antigens has been used in the treatment of patients with aml and mds (umin000011519) [26]. it is believed that as research progresses, more and more tcr-t treatments will be applied to the clinic.

remarks:
1.or: odds ratio or odds ratio, which is the ratio of the proportion of test factors in the positive reaction population to the proportion of test factors in the negative reaction population; or>1 indicates that the exposure is positively correlated with the disease, and the exposure has a higher incidence. hazard; or <1 indicates that exposure is negatively correlated with disease and exposure is protective.
2.☆☆☆☆☆: on behalf of this hla correlation has been very clear, guidelines, expert consensus, international and domestic has or need to carry out testing services;
☆☆☆: the hla correlation is not very clear and can be used as a research direction.
3.cpic: clinical pharmacogenetics implementation consortium clinical drug genomics implementation alliance
4. the correlation between hla and disease is not limited to the summary content. it has certain correlation in cardiovascular disease, kidney disease and blood system disease, but it has not formed an expert consensus and is still in the scientific research stage.

references:
[1] wu j, li j, li s, et al. association of hla-dqb1 polymorphisms with rheumatoid arthritis: a meta-analysis [j]. postgraduate medical journal, 2017, 93(1104): 618-625.
[2] jiang l, jiang d, han y, et al. association of hla-dpb1 polymorphisms with rheumatoid arthritis: a systemic review and meta-analysis [j]. international journal of surgery, 2018, 52: 98-104.
[3] zhang x, wang h, luo y, et al. hla-dq, dr allele polymorphism of type 1 diabetes in the ch