Activation induced deaminase: How much and where?

Activation induced deaminase (AID) plays a central role in adaptive immunity by initiating the processes of somatic hypermutation (SHM) and class switch recombination (CSR). On the other hand, AID also predisposes to lymphoma and plays a role in some autoimmune diseases, for which reasons AID expression and activity are regulated at various levels. Post-translational mechanisms regulating the amount and subcellular localization of AID are prominent in balancing AID physiological and pathological functions in B cells. Mechanisms regulating AID protein levels include stabilizing chaperones in the cytoplasm and proteins efficiently targeting AID to the proteasome within the nucleus. Nuclear export and cytoplasmic retention contribute to limit the amount of AID accessing the genome. Additionally, a number of factors have been implicated in AID active nuclear import. We review these intertwined mechanisms proposing two scenarios in which they could interact as a network or as a cycle for defining the optimal amount of AID protein. We also comparatively review the expression levels of AID necessary for its function during the immune response, present in different cancers as well as in those tissues in which AID has been implicated in epigenetic remodeling of the genome by demethylating DNA.     

Activation-induced cytidine deaminase (AID) is expressed in normal spermatogenesis but only infrequently in testicular germ cell tumours

Activation-induced cytidine deaminase (AID) is essential for somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin genes in antigen-dependent B-cell maturation. SHM is not restricted to immunoglobulin gene loci, raising the possibility of a function for AID in other cell types. In this study, it is shown that AID is expressed in spermatocytes in the human testis. AID was mostly cytoplasmic but nuclear AID was also observed in a proportion of cells, in keeping with the DNA deamination model of AID function. Intratubular germ cell neoplasia unclassified (IGCNU), the precursor lesion of testicular cancers, was AID-negative. Seminomas also lacked AID expression. Nuclear and cytoplasmic AID expression was observed in three of 32 mixed non-seminomatous germ cell tumours. The results provide evidence for a physiological role for AID outside the immune system. AID expression in spermatocytes points to a role in meiosis. It remains uncertain whether AID may also contribute to the genetic aberrations characteristically found in testicular germ cell tumours. The consistent absence of detectable AID expression in atypical spermatogonia of IGCNU and its rare expression in germ cell tumours suggest that continued expression of AID is not involved in the pathogenesis of germ cell tumours.     

Activation-induced cytidine deaminase: structure-function relationship as based on the study of mutants

Activation-induced cytidine deaminase (AID; gene symbol AICDA) is the key molecule required to induce immunoglobulin (Ig) class switch recombination (CSR) and somatic hypermutation (SHM) of the variable regions of Ig genes. Its deficiency causes a form of hyper-IgM (HIGM) syndrome. The study of natural AID mutants associated with HIGM as well as engineered mutants led to the characterization of the active domains of the protein. AID, through its cytidine deaminase activity, induces a targeted DNA lesion as an early step required for both CSR and SHM. Besides its cytidine deaminase activity, AID plays a further essential role in CSR, likely by recruiting CSR-specific cofactors by its C-terminus. A similar binding of SHM-specific cofactors to the N-terminal part is suggested by the functional characteristics of N(ter) AID artificial mutants. These data require confirmation in vivo. Finally, AID acts as a homo-, di-, or multimeric complex. Together, these data strongly suggest that AID, a master molecule for antibody diversification, exerts its activity on CSR not only as a cytidine deaminase enzyme but also as a docking protein, recruiting specific cofactors to a multimeric complex.     

CD11b regulates antibody class switching via induction of AID

The integrin CD11b, which is encoded by the integrin subunit alpha M (ITGAM), is primarily expressed on the surface of innate immune cells. Genetic variations in ITGAM are among the strongest risk factors for systemic lupus erythematosus, an autoimmune disease characterized by the presence of autoantibodies. However, the regulatory function of CD11b in the antibody responses remains unclear. Here, we report the induction of CD11b in activated B2 B cells and define its unexpected role in immunoglobulin heavy chain class switch recombination (CSR). LPS-activated B cells lacking CD11b yielded fewer IgG subtypes such as IgG1 and IgG2a in vitro, and immunization-dependent CSR and affinity maturation of antibodies were severely impaired in CD11b-deficient mice. Notably, we observed the reduced expression of activation-induced cytidine deaminase (AID), an enzyme that initiates CSR and somatic hypermutation, and ectopic expression of AID was sufficient to rescue the defective CSR of CD11b-deficient B cells. LPS-induced phosphorylation of NF-κB p65 and IκBα was attenuated in CD11b-deficient B cells, and hyperactivation of IκB kinase 2 restored the defective AID expression and CSR, which implied that CD11b regulates the NF-κB-dependent induction of AID. Overall, our experimental evidence emphasized the function of CD11b in antibody responses and the role of CD11b as a vital regulator of CSR.     

The cytoplasmic AID complex

Although AID fulfils its physiological function of diversifying antibody genes in the nucleus, most of the AID protein within the cell is found in a complex located in the cytoplasm. In this review, we summarize what is currently known about this cytoplasmic AID complex. Its size has been estimated to lie between 300 and 500kDa (sedimentation coefficient of 10-11S) and it comprises the abundant protein translation elongation factor 1α (eEF1A) as a major stoichiometric component. We speculate on the possible roles of this complex as well as of chaperones known to interact with AID in regulating the cytosolic retention of AID and its controlled release for import into the nucleus.     

肠道菌群在自身免疫性疾病中的研究进展

自身免疫性疾病(autoimmune disease,AID)通过自身产生抗体,导致免疫耐受失衡,而引起的一系列慢性炎症反应,甚至对机体组织造成损伤。目前AID发病率逐渐升高,而其确切的发病机制尚不明确。肠道菌群作为人体最大的"免疫器官",参与机体代谢,形成肠粘膜屏障,维持免疫功能正常。随着对人体肠道菌群研究的深入,越...     

The role of activation-induced deaminase in antibody diversification and genomic instability

More than a decade ago, activation-induced deaminase (AID) was identified as the initiator for somatic hypermutation (SHM) and class switch recombination (CSR). Since then, tremendous progress has been achieved toward elucidating how AID functions. AID targets the highly repetitive switch regions of the immunoglobulin heavy chain (IgH) locus to induce DNA double-strand breaks (DSBs), which can be rejoined, leading to switch of constant regions of antibody. When targeting to variable region exons of IgH and IgL loci, AID predominantly induces point mutations, termed SHM, resulting in increased affinity of antibody for antigen. While SHM and CSR enhance antibody diversity, AID-initiated DSBs and mutations may predispose B cells to carcinogenesis. This review focuses on the mechanisms that provide the specificity of AID targeting to Ig loci and the role of AID in genomic instability.     

斑点免疫金银染色检测RNA抗体及其临床意义

采用斑点免疫金银染色法检测了280份临床血清标本的抗RNA 抗体.其中144份血清同时以ELISA 法作平行对照。两法检测结果差异无显著性(P>0.05),符合率91%,两法定量结果间存在高度的直线正相关性。该抗体在自身免疫病中的检出率为46.6%,其中在SLE 达62%,但在非自身免疫病仅为5.1%,可作为自身免疫病筛查指标,对ANA 阴性者尤有意义。     

A role for activation-induced cytidine deaminase in the host response against a transforming retrovirus

Activation-induced cytidine deaminase (AID) is specifically expressed in the germinal centers of lymphoid organs, where it initiates targeted hypermutation of variable regions of immunoglobulin genes in response to stimulation by antigen. Ectopic expression of AID, however, mediates generalized hypermutation in eukaryotes and prokaryotes. Here, we present evidence that AID is induced outside the germinal center in response to infection by the Abelson murine leukemia virus. The genotoxic activity of virally induced AID resulted in checkpoint kinase-1 (chk1) phosphorylation and ultimately restricted the proliferation of the infected cell. At the same time, it induced NKG2D ligand upregulation, which alerts the immune system to the presence of virally transformed cells. Hence, in addition to its known function in immunoglobulin diversification, AID is active in innate defense against a transforming retrovirus.     

HSP90 inhibitors decrease AID levels and activity in mice and in human cells

Activation induced deaminase (AID) initiates somatic hypermutation and class switch recombination of the Ig genes in antigen‐activated B cells, underpinning antibody affinity maturation and isotype switching. AID can also be pathogenic by contributing to autoimmune diseases and oncogenic mutations. Moreover, AID can exert noncanonical functions when aberrantly expressed in epithelial cells. The lack of specific inhibitors prevents therapeutic applications to modulate AID functions. Here, we have exploited our previous finding that the HSP90 molecular chaperoning pathway stabilizes AID in B cells, to test whether HSP90 inhibitors could target AID in vivo. We demonstrate that chronic administration of HSP90 inhibitors decreases AID protein levels and isotype switching in immunized mice. HSP90 inhibitors also reduce disease severity in a mouse model of acute B‐cell lymphoblastic leukemia in which AID accelerates disease progression. We further show that human AID protein levels are sensitive to HSP90 inhibition in normal and leukemic B cells, and that HSP90 inhibition prevents AID‐dependent epithelial to mesenchymal transition in a human breast cancer cell line in vitro. Thus, we provide proof‐of‐concept that HSP90 inhibitors indirectly target AID in vivo and that endogenous human AID is widely sensitive to them, which could have therapeutic applications.     

MDR1基因多态性在自身免疫性疾病精准诊疗中的应用

自身免疫性疾病 (Autoimmune Disease,AID) 是因机体对自身抗原发生反应,免疫稳态失衡而引起自身组织损伤的疾病状态,与自身抗原、免疫调节异常、交叉抗原、遗传因素有关。AID 精准诊疗是目前 AID 临床管理的新方向。 多药耐药-1 (Multi-drug Resistance-1,MDR1) 基因多态性在 AID 的诊断和鉴别诊断,确定疾病活动、严重程度和并发症, 治疗方案选择及疗效预测等方面有良好的应用前景,并将有助于实现临床AID患者个体化管理。本文就MDR1基因多态性在常见AID精准诊疗中应用的研究进展做一综述。     

Seronegative autoimmune diseases: A challenging diagnosis

Autoimmune diseases (AID) are increasingly prevalent conditions which comprise more than 100 distinct clinical entities that are responsible for a great disease burden worldwide. The early recognition of these diseases is key for preventing their complications and for tailoring proper management. In most cases, autoantibodies, regardless of their potential pathogenetic role, can be detected in the serum of patients with AID, helping clinicians in making a definitive diagnosis and allowing screening strategies for early -and sometimes pre-clinical- diagnosis. Despite their undoubted crucial role, in a minority of cases, patients with AID may not show any autoantibody, a condition that is referred to as seronegative AID. Suboptimal accuracy of the available laboratory tests, antibody absorption, immunosuppressive therapy, immunodeficiencies, antigen exhaustion, and immunosenescence are the main possible determinants of seronegative AID. Indeed, in seronegative AID, the diagnosis is more challenging and must rely on clinical features and on other available tests, often including histopathological evaluation and radiological diagnostic tests. In this review, we critically dissect, in a narrative fashion, the possible causes of seronegativity, as well as the diagnostic and management implications, in several AID including autoimmune gastritis, celiac disease, autoimmune liver disease, rheumatoid arthritis, autoimmune encephalitis, myasthenia gravis, Sjögren’s syndrome, antiphospholipid syndrome, and autoimmune thyroid diseases.     

Immune hemolytic anemia induced by drugs

Drugs may induce immune destruction of red blood cells through either autoantibody formation or antibody formation against the drug or its metabolites. In the former scheme the drug is believed to induce autoimmunization by causing some central dysregulation of the immune system the mechanism of which is still unclear. In the latter, data have been accumulating during the last decade pertaining to clinical manifestations, incriminated drugs, and immunohematologic diagnosis. The sharp specificity and individual variations of drug specific antibodies as well as the recognition of the receptor role of red cell blood group antigens explaining the involvement of red cells in drug-antidrug complexes are among the recent achievements in the knowledge of these anemias.     

侵袭蛋白对双价志贺菌苗免疫保护影响的研究

为了研究侵袭蛋白与免疫保护的关系 ,为志贺菌苗的研制提供理论依据。经志贺菌苗角结膜免疫豚鼠 ,毒株攻击 ,观察侵袭蛋白对免疫保护的影响 ,观察到表达侵袭蛋白的菌苗较不表达侵袭蛋白的菌苗对毒株攻击有较高的保护率 ;用BA ELISA方法检测免疫后豚鼠泪液中特异性抗体水平 ,其结果较对照显著升高。说明侵袭蛋白的表达有一定的增加菌苗的免疫保护作用