Nature: The Tsinghua Bohai Task Force found a new mechanism for the difference between the sexes in the antibody immune response.

On December 26, Professor Qi Hai, from the Institute of immunology, Tsinghua University, published a report entitled "a gpr174-ccl21 module imparts sexual dimorphism to human" in nature In this paper, we found a new mechanism leading to the difference of antibody immune response between men and women, which provided new ideas and potential new targets for enhancing the effect of vaccination and the treatment of antibody mediated autoimmune diseases.the antibody is produced after B lymphocyte is stimulated by antigen and differentiated into plasma cell.in order to differentiate into plasma cells and produce more antibodies, B lymphocytes need to undergo a process called "affinity maturation" from the settlement called "follicle" area to the tissue structure called "germinal center".from follicles to germinal centers, B lymphocytes undergo a series of migration after antigen stimulation.these migration movements are regulated by a series of GPCR family receptors by sensing the distribution of different chemokines in lymphoid tissue.each chemokine corresponds to at least one GPCR receptor, and each GPCR receptor may produce different chemotaxis by coupling different GA proteins.therefore, the different distribution of chemokines in lymphoid tissue will lead to the migration of immune cells expressing corresponding receptors in different directions and with different intensities, and finally achieve different tissue distribution.for example, B cells express GPCR called CCR7, which are receptors for chemokines CCL21 and CCL19.under the stimulation of these two factors, CCR7 can couple Gai and promote the cells to move towards the direction with high concentration of chemokines.CCL21 and CCL19 are usually located in areas called T-cell areas, away from germinal centers. Br / >the expression of RCB is down-regulated in the primary cells of.for another example, there is a GPCR called s1pr2, which is stimulated by lipid ligand S1P and coupled with GA12 / 13, resulting in rejection, which makes B cells move away from the ligand.the concentration of S1P is the lowest in germinal center, so the expression of s1pr2 can promote B cells to enter the germinal center, and B cells activate to up regulate s1pr2 to prepare for entering germinal center.the researchers of Qihai group found that although there was no difference in the expression of GPCR (including CCR7 and s1pr2) that were known to affect the localization of germinal centers, the efficiency of reaching germinal centers was different between female and male B cells.female B cells aggregate more rapidly and more to germinal center than male B cells, participate more in affinity maturation process in germinal center, and produce more plasma cells and antibodies.none of the GPCRs known to affect B-cell chemotaxis has ever shown gender differences.these researchers found that B cells also expressed an X-linked gpr174 while searching for other GPCR that could affect the localization of germinal centers of B cells.although there was no previous report on the chemotaxis of gpr174, they found that gpr174 could affect the migration of B cells and make them more likely to locate in the T cell area away from the germinal center.to their surprise, the effect of gpr174 mainly occurred on male B cells, but had little effect on female B cells, although there was no difference in gpr174 expression between the sexes.this finding may explain why the ability of male and female B cells to reach and continue to participate in germinal centers is different.furthermore, they identified CCL21 as the chemokine acting on gpr174 by protein level separation and mass spectrometry.as mentioned above, CCL21 is a chemokine ligand of CCR7, and no other receptor has been found for more than 20 years.in vitro chemotaxis experiments demonstrated that gpr174-ccl21 did promote chemotaxis of male rather than female B cells in a receptor ligand manner.CCL21 was distributed in the T cell area far from the germinal center, which could explain why gpr174 could reduce the localization of male B cells to germinal center.then, why does the same gpr174 receptor act differently in male and female cells? The researchers of Qihai group found that androgen played a decisive role.when stimulated by CCL21, gpr174 in male cells can couple with a large number of Gai proteins, and promote male cells to chemotaxis to CCL21.gpr174 on female cells does not couple a lot of Gai, and so does male cells from testicular removed male mice; if female animals are artificially injected with androgen, female B cells will become like male B cells and begin to couple more Gai, thus more effectively chemotactic towards CCL21.finally, these researchers explored the effect of gpr174-ccl21 on antibody dependent autoimmune encephalomyelitis models.they found that male mice were less susceptible to this autoimmune disease, and their condition was reversed by knockout of the gpr174 gene in B cells: knockout mice became more like female mice, produced more autoantibodies, and got worse.on the contrary, gpr174 specific knockout on B cells did not affect the course of disease in female mice.these results are consistent with the ability of gpr174-ccl21 to regulate the localization of male and female B cells to germinal center.in summary, this study of Qihai group found a clear cellular immune mechanism for the difference of antibody immune response between male and female individuals, and opened up an unexpected new way to understand the characteristic of male and female differences shared by mammalian immune system. these researchers believe that gpr174 should not be the only mechanism that leads to gender differences. however, male individuals can rely on hormones to regulate the coupling efficiency of specific GPCR and GA protein in specific stages of immune response and on specific cells, so as to fine tune the antibody immune response to achieve a balance different from that of females, which makes us sigh at the ingenuity of nature. according to Qi Hai, they will further explore how hormones regulate GPCR GA protein coupling, how gpr174 and CCR7 cooperate or antagonize under the stimulation of CCL21 ligand, and how these processes affect the function of B cells and autoimmune diseases in the human body. they also hope to develop drugs for gpr174 and its related process mechanisms, so as to enhance the effect of vaccination. Professor Qi Hai's research group has been devoted to the research on the regulatory mechanism of antibody immune response and hair center reaction for a long time, and has published a series of original papers on the frontier scientific issues in the field such as nature and science. Zhao ruozhu, a doctoral student in 2013 of the Joint Center for life sciences, is the first author of this paper and undertakes the main experimental work. at the initial stage of the project, Dr. Chen Xin, a doctoral graduate of Tsinghua University School of medicine, and Ma Weiwei, a master graduate, have done a lot of exploration and preparation work in the initial stage of the project. Dr. Zhang Jinyu, postdoctoral of Tsinghua University Medical School, participated in the important experimental work in the later stage of the project. the project has received indispensable cooperation and support from many parties, including Zhou Xuyu research group of Institute of Microbiology, Chinese Academy of Sciences, Wang Jianbin research group of School of life sciences of Tsinghua University and Li Tao research group of Academy of military Medical Sciences. the platform of protein preparation and identification, proteomics and metabonomics provided technical support. the project is funded by the National Natural Science Foundation of China (NSFC) (projects 81621002, 31830023, 81761128019 and 81425011), Life Sciences Joint Center, Beijing Municipal Science and Technology Commission, Beijing biological structure frontier research center, and international researcher program of Howard Hughes Institute of medicine. gpr174-ccl21 module imparts semantic morphology to human immunity. for more information, please scan the QR code above