Humoral and Cellular Immunology in Human Prostate Cancer: Plasma Cells and T and B Lymphocytes / Inmunología Humoral y Celular en el Cáncer de Próstata Humano: Células Plasmáticas y Linfocitos T y B

SUMMARY: In solid and malignant tumors, innate and adaptive immunity are combined in antitumor responses. This study aimed to analyze the activation of plasma cells and the correlation between the infiltration of B and T lymphocytes with the degree of malignancy or Gleason grade in human prostate biopsies diagnosed with cancer. Prostate cancer biopsies were obtained from the Clinical Hospital of Universidad de Chile (n=70), according to the bioethical norms of the institution. Histological sections of 5µm thickness were processed for immunohistochemistry with primary antibodies against BL and total TL (HRP/DAB). Recognition and quantification were performed under a Leica DM750 optical microscope. Microsoft Excel and GraphPad software were used for the statistical study. Correlation coefficient (Pearson) and mean comparison tests (Kruskal-Wallis and Dunn) and p≤ 0.05 were developed. B and T lymphocyte populations were inversely interregulated in prostate cancer (Gleason) (r= -0.46). Their relationship with Gleason grade is variable according to lymphocyte type (LB vs. Gleason r= -0.0.47 and LT vs. Gleason r= -0.21). Histological diagnosis of prostate cancer correlates with a predominance of LT. The malignancy of the pathology correlates with a predominance of LTs, according to the Gleason grade. The increased knowledge of B and T lymphocyte infiltration and plasma cell activation could be used to better target clinical trials on treatments based on immune system responses. Immunotherapy could be a new paradigm to apply better antitumor therapy strategies.

En tumores sólidos y malignos, la inmunidad innata y adaptativa se combinan en respuestas antitumorales. Este estudio tuvo como objetivo analizar la activación de células plasmáticas y la correlación entre la infiltración de linfocitos B y T con el grado de malignidad o grado de Gleason en biopsias de próstata humana diagnosticadas con cáncer. Las biopsias de cáncer de próstata se obtuvieron del Hospital Clínico de la Universidad de Chile (n=70), de acuerdo con las normas bioéticas de la institución. Secciones histológicas de 5 µm de espesor fueron procesadas para inmunohistoquímica con anticuerpos primarios contra LB y LT total (HRP/DAB). El reconocimiento y las cuantificaciones se realizaron bajo un microscopio óptico Leica DM750. Para el estudio estadístico se utilizaron los programas Microsoft Excel y GraphPad. Se desarrollaron pruebas de coeficiente de correlación (Pearson) y comparación de medias (Kruskal-Wallis y Dunn) y p≤ 0.05. Los resultados muestran que las poblaciones de linfocitos B y T están inversamente interreguladas en el cáncer de próstata (r= -0,4578). Su relación con el grado de Gleason es variable según el tipo de linfocito (LB vs Gleason r= -0,47* y LT vs Gleason r= -0,21). Se concluye que la malignidad del cáncer de próstata se correlaciona con un predominio de LT, versus el grado de Gleason. El mayor conocimiento de la infiltración de linfocitos B y T y la activación de células plasmáticas podría aprovecharse para una mejor orientación de ensayos clínicos en tratamientos basados en las respuestas del sistema inmunitario. La inmunoterapia podría ser un nuevo paradigma para aplicar mejores estrategias de terapias antitumorales.

Respuesta inmunitaria anti-SARS-CoV-2: Infección Naturalvs. Vacunación / Anti-SARS-CoV-2 immune response: natural infection vs vaccination

Este trabajo es una revisión bibliográfica que compara la inmunidad anti-SARS-CoV-2 inducida por la infección natural y la inducida por vacunación, para entenderlas particularidades de la respuesta en cada caso, así como sus ventajas y desventajas. Se escogieron artículos que reportaran la medición de concentración de anticuerpos séricos, determinantes de inmunidad celular y/o evolución clínica de los pacientes. Se encontró que: A) Los pacientes recuperados de una infección por SARS-CoV-2 presentaron una respuesta mayor y más heterogénea de anticuerpos y células B de memoria que los pacientes vacunados, con un mayor número de linfocitos TCD4+, que cooperan con la diferenciación de linfocitos B y con la producción de anticuerpos neutralizantes. B) La vacunación previene la tormenta de citocinas asociada a la infección natural. C) Dos dosis de una vacuna basada en ARN mensajero logran una concentración de anticuerpos de clase IgG prácticamente igual a la de los pacientes severamente enfermos, pero sin el daño a los nódulos linfáticos asociado a la infección natural. D) Se puede aumentar el número de linfocitos B administrando dosis de refuerzo de la vacuna. Si bien, tanto la vacunación como la infección natural generan respuestas anti-SARS-CoV-2 significativas, la vacunación es el método más seguro para proteger a la población, pues evita el riesgo a la inmunopatología y a la mortalidad asociados con la infección natural. Más aún, la inmunidad híbrida (aquella que adquieren los pacientes que superaron la infección natural y fueron después vacunados) induce una producción de anticuerpos capaces de neutralizar por completo al SARS-CoV-2(AU)

This work is a bibliographic review that comparesanti-SARS-CoV-2 inmmune response induced by natural infección with that induced by vaccination, to understand theparticularities of each response, as well as their advantages and disadvantages. Research articles that reported levels of antibodies in serum, determinants of cellular inmmunity and/or clinical evolution of patients were chosen. It was found that: A) Pacients previously infected with SARS-CoV-2 presented a larger and more heterogeneous response of antibodies and memory B cells than vaccined patients, with a larger number of CD4+T cells that cooperate with the differentiation of B cells and production of neutralizing antibodies. B) Vaccination prevents the cytokine storm associated with natural infection. C) Two doses of an mRNA vaccine induced an IgG concentration nearly equal to severe ill patients but without the damage to lymph nodes associated with natural infection. D) B cell levels can be increased by giving booster doses of the vaccine. Althought both vaccination and natural infection generate significant anti-SARS-CoV-2 immune responses, vaccination is the safest method to protect general population, because it avoids the risk of immunopathology and mortality associated with natural infection. Futhermore, hybrid immunity (thatadquired by patients who overcame the natural infection and were later vaccinated), induces production of antibodies capable of completely neutralizing SARS-CoV-2(AU)

The Distribution and Significance of Activated T Cells and Lymphocyte Subsets in Myelodysplastic Syndrome / 中国实验血液学杂志

OBJECTIVE@#To investigate the distribution of bone marrow lymphocyte subsets in patients with myelodysplastic syndrome(MDS),the proportion of activated T cells with immunophenotype CD3+HLA-DR+ in the lymphocytes and its clinical significance, and to understand the effects of different types of MDS, different immunophenotypes, and different expression levels of WT1 on the proportion of lymphocyte subsets and activated T cells.@*METHODS@#The immunophenotypes of 96 MDS patients, the subsets of bone marrow lymphocytes and activated T cells were detected by flow cytometry. The relative expression of WT1 was detected by real-time fluorescent quantitative PCR, and the first induced remission rate (CR1) was calculated, the differences of lymphocyte subsets and activated T cells in MDS patients with different immunophenotype, different WT1 expression, and different course of disease were analyzed.@*RESULTS@#The percentage of CD4+T lymphocyte in MDS-EB-2, IPSS high-risk, CD34+ cells >10%, and patients with CD34+CD7+ cell population and WT1 gene overexpression at intial diagnosis decreased significantly (P<0.05), and the percentage of NK cells and activated T cells increased significantly (P<0.05), but there was no significant difference in the ratio of B lymphocytes. Compared with the normal control group, the percentage of NK cells and activated T cells in IPSS-intermediate-2 group was significantly higher(P<0.05), but there was no significant difference in the percentage of CD3+T, CD4+T lymphocytes. The percentage of CD4+T cells in patients with complete remission after the first chemotherapy was significantly higher than in patients with incomplete remission(P<0.05), and the percentage of NK cells and activated T cells was significantly lower than that in patients with incomplete remission (P<0.05).@*CONCLUSION@#In MDS patients, the proportion of CD3+T and CD4+T lymphocytes decreased, and the proportion of activated T cells increased, indicating that the differentiation type of MDS is more primitive and the prognosis is worse.

A review of progress in B cell receptor (BCR) antigen specificity / 细胞与分子免疫学杂志

B cell receptor (BCR) is a key molecule involved in B cell specific recognition and the binding of antigens to produce adaptive humoral immune response. Gene rearrangement and high frequency mutation during B cell differentiation are the main mechanisms of BCR diversification. The enormous diversity and unique molecular structure of BCR determine the diversity and specificity of antigen recognition, shaping complex B cell repertoire with extensive collections of antigen specificities. Therefore, BCR antigen-specific information is vital to understanding the adaptive immune characteristics of different diseases. Our ability to connect BCR repertoire and antigen specificity has been enhanced with the development of B cell related research technologies, such as single cell sorting techniques, high-throughput sequencing (HTS), linking B cell receptor to antigen specificity through sequencing (LIBRA-seq). It could help researchers to better understand humoral immune responses, identify disease pathogenesis, monitor disease progression, design vaccines, and develop therapeutic antibodies and drugs. We summarizes recent studies on antigen-specific BCR of infections, vaccinations, autoimmune diseases and cancer. By analyzing autoantibody sequences of SLE as a case, the identification of autoantigens has become potentially possible due to this characterization.

Activation-induced cytidine deaminase (AID) involved in the regulation of B cell immune senescence / 细胞与分子免疫学杂志

The humoral immune response of B cells is the key to the protection of specific immunity, and immune aging reshapes its production and function. The decreased B cell immune function is an indicator of immune senescence. The impaired humoral immune function mediated by antibody secreted by B cells leads to a decline in the response of elderly individuals to the vaccine. These people are therefore more susceptible to infection and deterioration, and have a higher incidence of tumors and metabolic diseases. Activation-induced cytidine deaminase (AID) is an enzyme that triggers immunoglobulin class conversion recombination (CSR) and somatic high frequency mutation (SHM). It decreases during immune senescence and is considered to be a biomarker of decreased B cell function in aging mice and humans. Understanding the inherent defects of B-cell immune senescence and the regulation mechanism of AID in the aging process can provide new research ideas for the susceptibility, prevention and treatment of diseases in the elderly.

Application of modified Matutes score containing CD200 in diagnosis of chronic lymphocytic leukemia / 中南大学学报(医学版)

OBJECTIVES@#Immunophenotyping technique is a powerful tool for the diagnosis and differential diagnosis of chronic lymphocytic leukemia (CLL) and other B-cell chronic lymphoproliferative diseases (B-CLPD). CD200 is strongly expressed in CLL. This study aims to analyze the clinical value of modified Matutes score (MMS) containing CD200 in the diagnosis of CLL.@*METHODS@#We retrospectively analyzed 103 B-CLPD patients diagnosed from January 2020 to July 2021, including 64 CLL patients, 11 follicular lymphoma (FL) patients, 14 mantle cell lymphoma (MCL) patients, 6 marginal zone lymphoma (MZL) patients, 1 hairy cell leukemia (HCL) patient, and 7 lymphoplasmic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) patients. The expression of CD markers between the CLL group and the non-CLL group was compared, and the sensitivity, specificity, and clinical consistency of MMS and Royal Marsden Hospital (RMH) immunophenotyping score system were analyzed.@*RESULTS@#There were significant differences in the expressions of CD5, CD23, FMC7, CD22, CD79b, CD200, and sIg between the CLL group and the non-CLL group (χ2 values were 37.42, 54.98, 30.71, 11.67, 55.26, 68.48, and 17.88, respectively, all P<0.01). When the RMH immunophenotyping score≥4, the sensitivity was 79.7%, and the specificity was 100%. When the MMS≥3, the sensitivity was 95.3%, and the specificity was 100%. The Kappa coefficient of RMH immunophenotyping system was 0.677, and the Kappa coefficient of MMS system was 0.860.@*CONCLUSIONS@#The MMS system containing CD200 has better sensitivity and same specificity compared with RMH immunophenotyping system, and MMS system may be more useful in the diagnosis of CLL.

B cells and tumor immune escape / 中南大学学报(医学版)

B lymphocyte is an important component of the human immune system and it has a role in the process of the body's specific immunity. In recent years, the research on B cells and tumor immune escape has rapidly progressed. Studies have shown that different types of B cells play different roles in tumor microenvironment through a variety of mechanisms. B cells in the tertiary lymphatic structure promote anti-tumor immunity, while regulatory B cells promote tumor immune escape. Antibody drugs targeting B cells are a promising direction for tumor immunotherapy.

Advances of using antibody against B cell activating factor for treatment of autoimmune diseases / 生物工程学报

In recent decades, the treatment of autoimmune diseases has moved from the use of hormones and conventional immunosuppressive drugs to biological agents. B cell proliferation and maturation play crucial roles in the development of autoimmune diseases. The tumor necrosis factor superfamily ligand B cell activating factor (BAFF) and its receptor mediate B cell survival through regulating signaling pathways. Therefore, BAFF and its receptors are important therapeutic targets for the treatment of autoimmune diseases. This review describes the mechanism of BAFF and its receptor in the human body system and introduces the latest views on how over-activation of BAFF pathway promotes the development of autoimmune diseases including systemic lupus erythematosus, Sjogren's syndrome, and rheumatoid arthritis. In connection to the treatment of the above three diseases, this review discusses the clinical trials and application status of three BAFF-targeting antibody drugs, including Belimumab, Tabalumab and Atacicept. Finally, this review proposes new strategies that targeting the BAFF pathway to provide a new treatment for autoimmune diseases.

A retrospective comparative study of haplotype hematopoietic stem cell transplantation and human leukocyte antigen-matched sibling donor hematopoietic stem cell transplantation in the treatment of acute B-lymphocyte leukemia / 中华血液学杂志

Objective: To investigate whether haplotype hematopoietic stem cell transplantation (haplo-HSCT) is effective in the treatment of pre transplant minimal residual disease (Pre-MRD) positive acute B lymphoblastic leukemia (B-ALL) compared with HLA- matched sibling donor transplantation (MSDT) . Methods: A total of 998 patients with B-ALL in complete remission pre-HSCT who either received haplo-HSCT (n=788) or underwent MSDT (n=210) were retrospectively analyzed. The pre-transplantation leukemia burden was evaluated according to Pre-MRD determinedusing multiparameter flow cytometry (MFC) . Results: Of these patients, 997 (99.9% ) achieved sustained, full donor chimerism. The 100-day cumulative incidences of neutrophil engraftment, platelet engraftment, and grades Ⅱ-Ⅳ acute graft-versus-host disease (GVHD) were 99.9% (997/998) , 95.3% (951/998) , and 26.6% (95% CI 23.8% -29.4% ) , respectively. The 3-year cumulative incidence of total chronic GVHD was 49.1% (95% CI 45.7% -52.4% ) . The 3-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) of the 998 cases were 17.3% (95% CI 15.0% -19.7% ) and 13.8% (95% CI 11.6% -16.0% ) , respectively. The 3-year probabilities of leukemia-free survival (LFS) and overall survival (OS) were 69.1% (95% CI 66.1% -72.1% ) and 73.0% (95% CI 70.2% -75.8% ) , respectively. In the total patient group, cases with positive Pre-MRD (n=282) experienced significantly higher CIR than that of subjects with negative Pre-MRD [n=716, 31.6% (95% CI 25.8% -37.5% ) vs 14.3% (95% CI 11.4% -17.2% ) , P<0.001]. For patients in the positive Pre-MRD subgroup, cases treated with haplo-HSCT (n=219) had a lower 3-year CIR than that of cases who underwent MSDT [n=63, 27.2% (95% CI 21.0% -33.4% ) vs 47.0% (95% CI 33.8% -60.2% ) , P=0.002]. The total 998 cases were classified as five subgroups, including cases with negative Pre-MRD group (n=716) , cases with Pre-MRD<0.01% group (n=46) , cases with Pre-MRD 0.01% -<0.1% group (n=117) , cases with Pre-MRD 0.1% -<1% group (n=87) , and cases with Pre-MRD≥1% group (n=32) . For subjects in the Pre-MRD<0.01% group, haplo-HSCT (n=40) had a lower CIR than that of MSDT [n=6, 10.0% (95% CI 0.4% -19.6% ) vs 32.3% (95% CI 0% -69.9% ) , P=0.017]. For patients in the Pre-MRD 0.01% -<0.1% group, haplo-HSCT (n=81) also had a lower 3-year CIR than that of MSDT [n=36, 20.4% (95% CI 10.4% -30.4% ) vs 47.0% (95% CI 29.2% -64.8% ) , P=0.004]. In the other three subgroups, the 3-year CIR was comparable between patients who underwent haplo-HSCT and those received MSDT. A subgroup analysis of patients with Pre-MRD<0.1% (n=163) was performed, the results showed that cases received haplo-HSCT (n=121) experienced lower 3-year CIR [16.0% (95% CI 9.4% -22.7% ) vs 40.5% (95% CI 25.2% -55.8% ) , P<0.001], better 3-year LFS [78.2% (95% CI 70.6% -85.8% ) vs 47.6% (95% CI 32.2% -63.0% ) , P<0.001] and OS [80.5% (95% CI 73.1% -87.9% ) vs 54.6% (95% CI 39.2% -70.0% ) , P<0.001] than those of MSDT (n=42) , but comparable in 3-year NRM [5.8% (95% CI 1.6% -10.0% ) vs 11.9% (95% CI 2.0% -21.8% ) , P=0.188]. Multivariate analysis showed that haplo-HSCT was associated with lower CIR (HR=0.248, 95% CI 0.131-0.472, P<0.001) , and superior LFS (HR=0.275, 95% CI 0.157-0.483, P<0.001) and OS (HR=0.286, 95% CI 0.159-0.513, P<0.001) . Conclusion: Haplo HSCT has a survival advantage over MSDT in the treatment of B-ALL patients with pre MRD<0.1% .

Uso clínico do rituximabe em doenças autoimunes / Clinical use of rituximab for autoimmune diseases

Doenças autoimunes são doenças universais, e os diagnósticos e tratamentos primários são habitualmente iniciados por clínicos em enfermarias ou ambulatórios, antes de serem encaminhados a especialistas. Além disso, pacientes em uso de biológicos internados em hospitais gerais têm sido cada vez mais frequentes na prática clínica. Conhecer o perfil de segurança, as indicações e os efeitos colaterais dessas drogas deve ser preocupação dos clínicos. Neste trabalho, foi realizada revisão de literatura sobre terapia biológica com rituximabe no tratamento das principais doenças autoimunes sistêmicas da prática clínica: artrite reumatoide, lúpus eritematoso sistêmico, vasculites relacionadas aos anticorpos anticitoplasma de neutrófilo, púrpura trombocitopênica imune e espondilite anquilosante. (AU)

AutoimmunAutoimmune diseases are universal diseases and primary diagnosis and treatment are typically initiated by internists in wards or outpatient clinics before being referred to specialists. In addition, patients on use of biologicals hospitalized in general hospitals have been increasingly common in clinical practice. Knowing the safety profile, the indications, and the side effects of these drugs should be a concern for the internists as well. In this study, the literature review was performed on biological therapy with Rituximab for treating the main systemic autoimmune diseases of clinical practice: rheumatoid arthritis, systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody-associated vasculitides, immune thrombocytopenic purpura, and ankylosing spondylitis. (AU)

Application of lymphocytes test in peripheral blood of patients with systemic sclerosis during the treatment / 北京大学学报(医学版)

OBJECTIVE@#To explore the significance of lymphocytes in systemic sclerosis (SSc), by detecting the levels of T lymphocytes, B lymphocytes and natural killer (NK) cells, and analyzing the correlation between the lymphocytes and clinical laboratory indexes.@*METHODS@#The numbers and proportion of T, CD4+T, CD8+T, B, and NK cells were detected by flow cytometry in peripheral blood of 32 SSc patients who had taken immunosuppressive drugs and 30 healthy controls (HC). The comparison of the lymphocyte subsets in SSc with them in the HC groups, and the correlation between the lymphocytes and other clinical and laboratory indicators were analyzed by the relevant statistical analysis.@*RESULTS@#Compared with the HC group, the numbers of T, CD4+T, CD8+T, and NK cells in peripheral blood of SSc group, who had taken immunosuppressive drugs, were significantly decreased (P < 0.05). More-over, the proportion of NK cells in peripheral blood of the SSc group was also significantly lower than that in the HC group (P=0.004). In addition, all the lymphocyte subsets were decreased in peripheral blood of more than 65% of the SSc patients who had taken immunosuppressive drugs. Compared with CD4+T normal group, the positivity of Raynaud's phenomenon, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) was significantly increased in CD4+T reduction group, respectively (P＝0.024, P < 0.001, P=0.018). ESR was higher in CD8+T reduction group than CD8+T normal group (P＝0.022). The prevalence of fingertip ulcer was significantly increased in B cell decrease group (P=0.019). Compared with NK cell normal group, the prevalence of fingertip ulcer was significantly increased in NK cell lower group (P=0.033), IgM was remarkablely decreased yet (P=0.049). The correlation analysis showed that ESR was negatively correlated with the counts of T lymphocytes (r＝－0.455, P＝0.009), CD4+T lymphocytes (r＝－0.416, P＝0.018), CD8+T lymphocytes (r＝－0.430, P=0.014), B cells (r＝－0.366, P＝0.039).@*CONCLUSION@#The number of CD4+T, CD8+T, B, and NK cells significantly decreased in peripheral blood of SSc patients who had used immunosuppressive drugs, some lymphocyte subsets might be related with Raynaud's phenomenon and fingertip ulcer, and reflected the disease activity by negatively correlated with ESR and CRP; the numbers of lymphocyte subsets in peripheral blood should be detected regularly in SSc patients who had taken immunosuppressive drugs.

Late recurrence of Burkitt's lymphoma in the jaw: numb chin syndrome as the only symptom

The Numb Chin Syndrome (NCS) is defined as facial and oral numbness restricted to the mental nerve's distribution involving the lower lip, skin of the chin, or gingiva of the lower anterior teeth. Hypoesthesia can occur unilaterally or bilaterally. Although this syndrome is rare, its importance is related to the fact that it represents the clinical manifestations of malignant diseases. Breast cancer and non-Hodgkin lymphoma are the most common cause of NCS. The patient, a 58-year-old woman, treated for a Burkitt Lymphoma (BL) nine years ago, described a two-week history of change in sensitivity and pain in the chin region, without relief with the use of analgesics. She had no headache, speech disturbance, dysphagia, visual disturbance, or other neurological symptoms. No surgical intervention has been performed recently. The intraoral examination revealed a healthy oral mucosa and a small area adjacent to the right mental nerve region that was uncomfortable to palpation. No changes were found in the bone trabeculae at cone-beam computed tomography. The contrasted magnetic resonance features made it possible to identify a change in the mandibular body extending to the entire right side, coinciding with the patient's complaint, indicating a probable mandibular medullary invasion. The patient was submitted to a biopsy to rule out a possible recurrence of BL. The microscopic findings were consistent with the diagnosis of BL. The present report described a very unusual presentation of late recurrent BL nine years after the first treatment, which manifested as an NCS.

Human follicular helper T lymphocytes critical players in antibody responses / Linfócitos T auxiliares foliculares humanos: células essenciais para a resposta de anticorpos

ABSTRACT Follicular helper T lymphocytes are a subpopulation of CD4+ T lymphocytes initially identified in germinal centers of follicles found in secondary lymphoid organs. The primary function of follicular helper T lymphocytes is to help B lymphocytes' antibody production. Changing of antibody class and affinity, B cell differentiation and memory generation depend on cooperation between follicular helper T lymphocytes and B cells. In blood, follicular helper T lymphocytes are called circulating follicular helper T lymphocytes. They are considered to have specificities similar to those developed in the secondary lymphoid organs. The phenotype of human follicular helper T lymphocytes is given by simultaneous expression of the markers CXCR5, Bcl-6, CD40L, PD-1, and ICOS. In germinal centers, follicular helper T lymphocytes synthesize interleukin 21 as predominant cytokine. In blood, subpopulations of circulating follicular helper T lymphocytes can be recognized, with different expressions of the classical follicular helper T lymphocytes markers and, in addition, can express other markers such as CXCR3 and CCR6. Presently, there is great interest in follicular helper T lymphocytes and circulating follicular helper T lymphocytes in vaccination studies as indicators of immunization efficacy. In addition, follicular helper T lymphocytes are investigated as possible markers of activity in many diseases and potential therapeutic intervention. This short review describes aspects of immunobiology and quantification of follicular helper T lymphocytes and circulating follicular helper T lymphocytes, and presents a few examples of related findings in systemic lupus erythematosus, rheumatoid arthritis, HIV infection and vaccination.

RESUMO Linfócitos T auxiliares foliculares são uma subpopulação de linfócitos T CD4+ identificada inicialmente nos centros germinativos dos folículos dos órgãos linfoides secundários. Sua função primordial é auxiliar os linfócitos B na produção de anticorpos. A mudança de classe e de afinidade dos anticorpos, a diferenciação das células B e a geração de memória dependem da cooperação entre os linfócitos T auxiliares foliculares e as células B. No sangue, recebem o nome de linfócitos T auxiliares circulantes. Considera-se que possuem especificidades semelhantes às desenvolvidas nos órgãos linfoides secundários. O fenótipo dos linfócitos T auxiliares humanos é dado pela expressão conjunta dos marcadores CXCR5, Bcl-6, CD40L, PD-1 e ICOS. Nos folículos, linfócitos T auxiliares sintetizam a interleucina 21 como citocina predominante. No sangue, são descritas várias subpopulações de linfócitos T auxiliares circulantes com expressões variadas dos marcadores clássicos de linfócitos T auxiliares, além de poderem agregar outros, como CXCR3 e CCR6. Existe um enorme interesse no estudo de linfócitos T auxiliares e linfócitos T auxiliares circulantes, para a avaliação de eficácia de vacinação. São também investigados como possíveis marcadores de atividade em muitas doenças e potenciais intervenções terapêuticas. Esta breve revisão descreve aspectos da imunobiologia e da quantificação de linfócitos T auxiliares humanos e linfócitos T auxiliares circulantes, além de apresentar alguns achados relacionados em lúpus eritematoso sistêmico, artrite reumatoide, infecção por HIV e vacinação.

Emerging molecular subtypes and therapeutic targets in B-cell precursor acute lymphoblastic leukemia / 医学前沿

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by genetic alterations with high heterogeneity. Precise subtypes with distinct genomic and/or gene expression patterns have been recently revealed using high-throughput sequencing technology. Most of these profiles are associated with recurrent non-overlapping rearrangements or hotspot point mutations that are analogous to the established subtypes, such as DUX4 rearrangements, MEF2D rearrangements, ZNF384/ZNF362 rearrangements, NUTM1 rearrangements, BCL2/MYC and/or BCL6 rearrangements, ETV6-RUNX1-like gene expression, PAX5alt (diverse PAX5 alterations, including rearrangements, intragenic amplifications, or mutations), and hotspot mutations PAX5 (p.Pro80Arg) with biallelic PAX5 alterations, IKZF1 (p.Asn159Tyr), and ZEB2 (p.His1038Arg). These molecular subtypes could be classified by gene expression patterns with RNA-seq technology. Refined molecular classification greatly improved the treatment strategy. Multiagent therapy regimens, including target inhibitors (e.g., imatinib), immunomodulators, monoclonal antibodies, and chimeric antigen receptor T-cell (CAR-T) therapy, are transforming the clinical practice from chemotherapy drugs to personalized medicine in the field of risk-directed disease management. We provide an update on our knowledge of emerging molecular subtypes and therapeutic targets in BCP-ALL.

Clinical Characteristics and Prognostic Factors of Primary FL Patients with Grade 3 or Large B Cell Transformation / 中国实验血液学杂志

OBJECTIVE@#To investigate the clinical characteristics and prognostic factors of primary follicular lymphoma (FL) patients with grade 3 or large B cell transformation, so as to provide more reference for the subsequent clinical diagnosis and treatment.@*METHODS@#Forty-seven primary FL patients with grade 3 or large B cell transformation from March 2010 to March 2018 were selected, the clinical characteristics and survival of patients were analyzed. Cox regression model were used to evaluate the related prognostic factors.@*RESULTS@#The cumulative progression-free survival rate and cumulative overall survival rate of 47 patients in 3-year follow-up reached to 55.32% (26/47) and 80.85% (38/47) respectively. There were significant differences in cumulative progression-free survival rate and cumulative overall survival rate among different subgroups of IPI, FLIPI-1 and FLIPI-2 in 3-year follow-up (P3 cm lymph node-involved site number≥3, extranodal lesion site number≥2, IPI score=2-3, FLIPI-1 score and FLIPI-2 score≥3 were the risk factors for progression-free survival (P<0.05); LDH≥240 U/ml, IPI score=2-3 and FLIPI-2 score≥3 were risk factors for overall survival (P<0.05). Cox regression model multivariate analysis showed that IPI score=2-3 was the independent risk factor for progression-free survival and overall survival (P<0.05). FLIPI-2 score≥3 was the independent risk factor for overall survival (P<0.05).@*CONCLUSION@#Primary FL patients with grade 3 or large B cell transformation by using the existing treatment regimen might be possibly curable, and the current treatment strategies and IPI score can be used to predict the clinical prognosis of patients.

Anti-CD19 CART (C-CAR011) Therapy for Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma / 中国实验血液学杂志

OBJECTIVE@#To evaluate the safety and efficacy of C-CAR011 in the treatment of relapsed or refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) patients.@*METHODS@#B-NHL patients treated with C-CAR011 infusion following lympho-depletion were enrolled. All the patients were followed up for 1 year after C-CAR011 treatment(5.0×10@*RESULTS@#The ratio of the male and female of 6 patients was 1∶1, and the patients were treated with C-CAR011 at a dose of 5.0×10@*CONCLUSION@#C-CAR011 is a safe treatment option for R/R B-NHL; some patients could achieve long-term sustained responses after C-CAR011 infusion（ClinicalTiral.gov number, NCT03483688）.

Mechanism of Xinfeng Capsules improving rheumatoid arthritis based on CD19~+B cells regulating FAK/CAPN/PI3K pathway / 中国中药杂志

To observe the effect of Xinfeng Capsules on rheumatoid arthritis (RA) B lymphocytes,inflammatory mediators,FAK/CAPN/PI3K pathway,in order to explore the mechanism of Xinfeng Capsules in improving clinical symptoms of RA.Joint and systemic symptoms of RA patients were observed,and laboratory indicators[hemoglobin (HGB),platelet count (PLT),erythrocyte sedimentation (ESR),immunoglobulin (Ig) G,Ig A,Ig M,rheumatoid factor (RF),anti-cyclic citrulline antibody (CCP-AB),C-reactive protein (CRP)]were detected.ELISA was used to detect serum interleukin (IL)-1β，IL-10,IL-33,chemokine 5 (CCL5),and vascular endothelial growth factor (VEGF).CD3~-CD19~+B cells were measured by flow cytometry.Western blot was used to detect FAK,p-FAK,CAPN,PI3K protein.The results showed that Xinfeng Capsules could significantly alleviate RA joint and systemic symptoms and improve clinical efficacy.And Xinfeng Capsules could increase HGB,decrease PLT,CCP-AB,CRP,ESR index,upregulate IL-10 expression,and down-regulate IL-1β，IL-33,CCL5,VEGF,CD3~-CD19~+B cells,FAK,p-FAK,CAPN,PI3K expressions (P<0.01).Based on the above results,Xinfeng Capsules may reduce the expression of CD3~-CD19~+,regulate the balance of inflammatory cytokines and chemokines,inhibit abnormal activation of FAK/CAPN/PI3K pathway,and improve clinical symptoms of RA.

Research progress in the rapid preparation of monoclonal antibodies of mouse hybridoma / 生物工程学报

Mouse hybridoma monoclonal antibody is the most commonly used antibody in immunology because of its stable source, easy preparation in later stage and high yield. The traditional time-consuming and laborious hybridoma preparation technology could not meet the growing market demand. In this paper, we describe the rapid preparation techniques involved in antigen design and screening, B cell enrichment and screening, transgenic myeloma cells, fusion technology improvement, positive hybridoma cell screening and rapid detection of monoclonal antibody performance, to provide a reference for rapid preparation of mouse hybridoma monoclonal antibody.

Advances in immortalization of human B cells / 生物工程学报

With the advantages of low immunogenicity and long half-life, human monoclonal antibody has become an indispensable biological agent in vivo. Immortalization of human B cells is a potential and effective method to obtain natural human antibody library, which can provide a rich source for the preparation of human monoclonal antibodies. As there are urgent problems to be solved in each platform, the preparation of antibodies based on human B cell immortalization is still limited to the laboratory research stage. At present, there is a lack of a systematic review to clarify the advantages and disadvantages of the existing human B cell immortalization antibody preparation platform and its feasibility analysis. This paper reviews the research on the preparation of human monoclonal antibody based on human B cells immortalization, and describes an in vitro cell culture method, in which hCD40L vesicles are used instead of feeder cells, in order to provide references for the further development of human monoclonal antibody preparation technology.

A risk score system for stratifying the risk of relapse in B cell acute lymphocytic leukemia patients after allogenic stem cell transplantation / 中华医学杂志(英文版)

BACKGROUND@#For patients with B cell acute lymphocytic leukemia (B-ALL) who underwent allogeneic stem cell transplantation (allo-SCT), many variables have been demonstrated to be associated with leukemia relapse. In this study, we attempted to establish a risk score system to predict transplant outcomes more precisely in patients with B-ALL after allo-SCT.@*METHODS@#A total of 477 patients with B-ALL who underwent allo-SCT at Peking University People's Hospital from December 2010 to December 2015 were enrolled in this retrospective study. We aimed to evaluate the factors associated with transplant outcomes after allo-SCT, and establish a risk score to identify patients with different probabilities of relapse. The univariate and multivariate analyses were performed with the Cox proportional hazards model with time-dependent variables.@*RESULTS@#All patients achieved neutrophil engraftment, and 95.4% of patients achieved platelet engraftment. The 5-year cumulative incidence of relapse (CIR), overall survival (OS), leukemia-free survival (LFS), and non-relapse mortality were 20.7%, 70.4%, 65.6%, and 13.9%, respectively. Multivariate analysis showed that patients with positive post-transplantation minimal residual disease (MRD), transplanted beyond the first complete remission (≥CR2), and without chronic graft-versus-host disease (cGVHD) had higher CIR (P  < 0.001, P = 0.004, and P  < 0.001, respectively) and worse LFS (P  < 0.001, P = 0.017, and P  < 0.001, respectively), and OS (P  < 0.001, P = 0.009, and P  < 0.001, respectively) than patients without MRD after transplantation, transplanted in CR1, and with cGVHD. A risk score for predicting relapse was formulated with the three above variables. The 5-year relapse rates were 6.3%, 16.6%, 55.9%, and 81.8% for patients with scores of 0, 1, 2, and 3 (P  < 0.001), respectively, while the 5-year LFS and OS values decreased with increasing risk score.@*CONCLUSION@#This new risk score system might stratify patients with different risks of relapse, which could guide treatment.