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Posts Tagged ‘B-cell’


Newly Found Functions of B Cell

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

The importance of B cells to human health is more than what is already known. Vaccines capable of eradicating disease activate B cells, cancer checkpoint blockade therapies are produced using B cells, and B cell deficiencies have devastating impacts. B cells have been a subject of fascination since at least the 1800s. The notion of a humoral branch to immunity emerged from the work of and contemporaries studying B cells in the early 1900s.

 

Efforts to understand how we could make antibodies from B cells against almost any foreign surface while usually avoiding making them against self, led to Burnet’s clonal selection theory. This was followed by the molecular definition of how a diversity of immunoglobulins can arise by gene rearrangement in developing B cells. Recombination activating gene (RAG)-dependent processes of V-(D)-J rearrangement of immunoglobulin (Ig) gene segments in developing B cells are now known to be able to generate an enormous amount of antibody diversity (theoretically at least 1016 possible variants).

 

With so much already known, B cell biology might be considered ‘‘done’’ with only incremental advances still to be made, but instead, there is great activity in the field today with numerous major challenges that remain. For example, efforts are underway to develop vaccines that induce broadly neutralizing antibody responses, to understand how autoantigen- and allergen-reactive antibodies arise, and to harness B cell-depletion therapies to correct non-autoantibody-mediated diseases, making it evident that there is still an enormous amount we do not know about B cells and much work to be done.

 

Multiple self-tolerance checkpoints exist to remove autoreactive specificities from the B cell repertoire or to limit the ability of such cells to secrete autoantigen-binding antibody. These include receptor editing and deletion in immature B cells, competitive elimination of chronically autoantigen binding B cells in the periphery, and a state of anergy that disfavors PC (plasma cell) differentiation. Autoantibody production can occur due to failures in these checkpoints or in T cell self-tolerance mechanisms. Variants in multiple genes are implicated in increasing the likelihood of checkpoint failure and of autoantibody production occurring.

 

Autoantibodies are pathogenic in a number of human diseases including SLE (Systemic lupus erythematosus), pemphigus vulgaris, Grave’s disease, and myasthenia gravis. B cell depletion therapy using anti-CD20 antibody has been protective in some of these diseases such as pemphigus vulgaris, but not others such as SLE and this appears to reflect the contribution of SLPC (Short lived plasma cells) versus LLPC (Long lived plasma cells) to autoantibody production and the inability of even prolonged anti-CD20 treatment to eliminate the later. These clinical findings have added to the importance of understanding what factors drive SLPC versus LLPC development and what the requirements are to support LLPCs.

 

B cell depletion therapy has also been efficacious in several other autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes, and rheumatoid arthritis (RA). While the potential contributions of autoantibodies to the pathology of these diseases are still being explored, autoantigen presentation has been posited as another mechanism for B cell disease-promoting activity.

 

In addition to autoimmunity, B cells play an important role in allergic diseases. IgE antibodies specific for allergen components sensitize mast cells and basophils for rapid degranulation in response to allergen exposures at various sites, such as in the intestine (food allergy), nose (allergic rhinitis), and lung (allergic asthma). IgE production may thus be favored under conditions that induce weak B cell responses and minimal GC (Germinal center) activity, thereby enabling IgE+ B cells and/or PCs to avoid being outcompeted by IgG+ cells. Aside from IgE antibodies, B cells may also contribute to allergic inflammation through their interactions with T cells.

 

B cells have also emerged as an important source of the immunosuppressive cytokine IL-10. Mouse studies revealed that B cell-derived IL-10 can promote recovery from EAE (Experimental autoimmune encephalomyelitis) and can be protective in models of RA and type 1 diabetes. Moreover, IL-10 production from B cells restrains T cell responses during some viral and bacterial infections. These findings indicate that the influence of B cells on the cytokine milieu will be context dependent.

 

The presence of B cells in a variety of solid tumor types, including breast cancer, ovarian cancer, and melanoma, has been associated in some studies with a positive prognosis. The mechanism involved is unclear but could include antigen presentation to CD4 and CD8 T cells, antibody production and subsequent enhancement of presentation, or by promoting tertiary lymphoid tissue formation and local T cell accumulation. It is also noteworthy that B cells frequently make antibody responses to cancer antigens and this has led to efforts to use antibodies from cancer patients as biomarkers of disease and to identify immunotherapy targets.

 

Malignancies of B cells themselves are a common form of hematopoietic cancer. This predilection arises because the gene modifications that B cells undergo during development and in immune responses are not perfect in their fidelity, and antibody responses require extensive B cell proliferation. The study of B cell lymphomas and their associated genetic derangements continues to be illuminating about requirements for normal B cell differentiation and signaling while also leading to the development of targeted therapies.

 

Overall this study attempted to capture some of the advances in the understanding of B cell biology that have occurred since the turn of the century. These include important steps forward in understanding how B cells encounter antigens, the co-stimulatory and cytokine requirements for their proliferation and differentiation, and how properties of the B cell receptor, the antigen, and helper T cells influence B cell responses. Many advances continue to transform the field including the impact of deep sequencing technologies on understanding B cell repertoires, the IgA-inducing microbiome, and the genetic defects in humans that compromise or exaggerate B cell responses or give rise to B cell malignancies.

 

Other advances that are providing insight include:

  • single-cell approaches to define B cell heterogeneity,
  • glycomic approaches to study effector sugars on antibodies,
  • new methods to study human B cell responses including CRISPR-based manipulation, and
  • the use of systems biology to study changes at the whole organism level.

With the recognition that B cells and antibodies are involved in most types of immune response and the realization that inflammatory processes contribute to a wider range of diseases than previously believed, including, for example, metabolic syndrome and neurodegeneration, it is expected that further

  • basic research-driven discovery about B cell biology will lead to more and improved approaches to maintain health and fight disease in the future.

 

References:

 

https://www.cell.com/cell/fulltext/S0092-8674(19)30278-8

 

https://onlinelibrary.wiley.com/doi/full/10.1002/hon.2405

 

https://www.pnas.org/content/115/18/4743

 

https://onlinelibrary.wiley.com/doi/full/10.1111/all.12911

 

https://cshperspectives.cshlp.org/content/10/5/a028795

 

https://www.sciencedirect.com/science/article/abs/pii/S0049017218304955

 

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Reporter: Aviva Lev-Ari, PhD, RN

Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility

Nature 496, 523–527 (25 April 2013)

 

24 April 2013

Germinal centres support antibody affinity maturation and memory formation1. Follicular T-helper cells promote proliferation and differentiation of antigen-specific B cells inside the follicle23. A genetic deficiency in the inducible co-stimulator (ICOS), a classic CD28 family co-stimulatory molecule highly expressed by follicular T-helper cells, causes profound germinal centre defects45, leading to the view that ICOS specifically co-stimulates the follicular T-helper cell differentiation program267. Here we show that ICOS directly controls follicular recruitment of activated T-helper cells in mice. This effect is independent from ICOS ligand (ICOSL)-mediated co-stimulation provided by antigen-presenting dendritic cells or cognate B cells, and does not rely on Bcl6-mediated programming as an intermediate step. Instead, it requires ICOSL expression by follicular bystander B cells, which do not present cognate antigen to T-helper cells but collectively form an ICOS-engaging field. Dynamic imaging reveals ICOS engagement drives coordinated pseudopod formation and promotes persistent T-cell migration at the border between the T-cell zone and the B-cell follicle in vivo. When follicular bystander B cells cannot express ICOSL, otherwise competent T-helper cells fail to develop into follicular T-helper cells normally, and fail to promote optimal germinal centre responses. These results demonstrate a co-stimulation-independent function of ICOS, uncover a key role for bystander B cells in promoting the development of follicular T-helper cells, and reveal unsuspected sophistication in dynamic T-cell positioning in vivo.

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Author: Tilda Barliya PhD

Acute lymphoblastic leukemia (ALL), a malignant disorder of lymphoid progenitor cells, affects both children and adults,
with peak prevalence between the ages of 2 and 5 years (2). Acute lymphocytic leukemia (ALL) is a heterogeneous disease, both in terms of its pathology and the populations that it affects. Disease pathogenesis involves a number of deregulated pathways controlling cell proliferation, differentiation, and survival that are important determinants of treatment response (3). Approximately 5200 new cases of ALL are estimated to have occurred in the United States in 2007 and survival varies with age and disease biology (3). Although five-year survival rates for ALL approach 90 percent with available chemotherapy treatments, the harmful side effects of the drugs, including secondary cancers and fertility, cognitive, hearing, and developmental problems, present significant concern for survivors and their families.

Biological and Clinical Prognostic Factors in ALL: Setting the Stage for Risk-Adapted Therapy

Of the many variables that influence prognosis the genetic subsets, initial white blood cell count (WBC), age at diagnosis, and early treatment response are the most important.

Childhood Acute Lymphoblastic Leukemia

Pathobiology

Acute lymphoblastic leukaemia is thought to originate  from various important genetic lesions in blood-progenitor  cells that are committed to differentiate in the T-cell or B-cell pathway, including mutations that impart the  capacity for unlimited self-renewal and those that lead to  precise stage-specific developmental arrest. In some  cases, the first mutation along the multistep pathway to  overt acute lymphoblastic leukaemia might arise in a  haemopoietic stem cell possessing multilineage developmental capacity.

The dominant theme of contemporary research in pathobiology of acute lymphoblastic leukaemia is to understand the outcomes of frequently arising genetic lesions, in terms of their effects on cell proliferation, differentiation, and survival, and then to devise selectively targeted treatments against the altered gene products to which the leukaemic clones have become addicted (2).

Table 1.

Prognostic factors used in pediatric and adult clinical trials

The Table  illustrates the different prognostic factors in children and adults that may be used for risk stratification in current clinical trials (3).

Genetics

  • Chromosomal translocations that activate specifi c genes
    are a defi ning characteristic of human leukaemias and
    of acute lymphoblastic leukaemia in particular.
  • About 25% of cases of B-cell precursor acute lymphoblastic leukaemia, the most frequent form of acute leukaemia in children, harbour the TEL-AML1 fusion gene—generated by the t(12;21)(p13;q22) chromosomal translocation.

The presence of the TEL-AML1 fusion
protein in B-cell progenitors seems to lead to disordered
early B-lineage lymphocyte development, a hallmark of
leukaemic lymphoblasts.

Analysis of TEL-AML1-induced cord blood cells suggests that the fusion gene serves as a first-hit mutation by endowing the preleukemic cell with altered self-renewal and survival properties.

  • In adults, the most frequent chromosomal translocation  is t(9;22), or the Philadelphia chromosome, which causes  fusion of the BCR signalling protein to the ABL  non-receptor tyrosine kinase, resulting in constitutive  tyrosine kinase activity and complex interactions of this  fusion protein with many other transforming elements.  BCR-ABL off ers an attractive therapeutic  target, and imatinib mesilate, a small-molecule inhibitor  of the ABL kinase, has proven effective against leukaemias that express BCR-ABL
  • More than 50% of cases of T-cell acute lymphoblastic  leukaemia have activating mutations that involve  NOTCH1. NOTCH1, which translocates to the nucleus and regulates by transcription a diverse set of responder genes, including the MYC oncogene.  The precise  mechanisms by which aberrant NOTCH signalling (due  to mutational activation) causes T-cell acute lymphoblastic  leukaemia are still unclear but probably entail constitutive  expression of oncogenic responder genes, such as MYC,  and cooperation with other signalling pathways (pre-TCR  [T-cell receptor for antigen] and RAS, for example).  Interference with NOTCH signalling by small-molecule  inhibition of γ-secretase activity has the potential to induce remission of T-cell acute lymphoblastic  leukemia.

Additionally A recent discussion has aimed to reveal the genetic origin of the disease (1). Several of these genes, including ARID5B, IKZF1, and CEBPE, have been implicated in processes such as hematopoietic differentiation and development of ALL. These gene obviously adds up to a number of other gene mutations and translocation already discovered and are associated with disease progression (2)  “The fact that alterations in these genes lead to ALL raises the question of what would happen if we restore these pathways in ALL and also make them possible exciting therapeutic targets as well.”

Nanotechnology and therapeutic

Dr. Rajasekaran, director and head of the Membrane Biology Laboratory University of Delaware,  says that there are currently seven or eight drugs that are used for chemotherapy to treat leukemia in children. They are all toxic and do their job by killing rapidly dividing cells. these drugs don’t differentiate cancer cells from other healthy cells. “The good news is that these drugs are 80 to 90 percent effective in curing leukemia. The bad news is that many chemotherapeutic treatments cause severe side effects, especially in children.  In preclinical models of leukemia, Dr. Rajasekaran research team have created NP  with an average diameter of 110 nm were assembled from an amphiphilic block copolymer of poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) bearing pendant cyclic ketals (ECT2). The researches have been encapsulated with dexamethasone as one third of the typical dose, with good treatment results and no discernible side effects.In addition, the mice that received the drugs delivered via nanoparticles survived longer than those that received the drug administered in the traditional way (4).

In another preclinical study Uckun F et al  developed nanoparticle (NP) constructs of WHI-P131. WHI-P131 (CAS 202475-60-3) is a dual-function inhibitor of JAK3 tyrosine kinase that demonstrated potent in vivo anti-inflammatory and anti-leukemic activity in several preclinical animal models (5). Notably, WHI-P131-NP was capable of causing apoptotic death in primary leukemia cells from chemotherapy-resistant acute lymphoblastic leukemia (ALL) as well as chronic lymphocytic leukemia (CLL) patients. WHI-P131-NP was also active in the RS4;11 SCID mouse xenograft model of chemotherapy-resistant B-lineage ALL. The life table analysis showed that WHI-P131-NP was more effective than WHI-P131 (P = 0.01), vincristine (P<0.0001), or vehicle (P<0.0001). These experimental results demonstrate that the nanotechnology-enabled delivery of WHI-P131 shows therapeutic potential against leukemias with constitutive activation of the JAK3-STAT3/STAT5 molecular target (5).

Summary:

Acute Lymphoblastic Leukemia (ALL) is a pediatric type of cancer that affects adults to lesser degree. The current rate of cure if 80% in  children whereas in adults only 30-40% will survive. Much of the success is due to understanding the mechanisms that lead to the development and progression of cancer. Several gene mutations and gene-translocation have already been identified,  and targeting them enabled some of the major success in curing these kids.

Thus far, nanotechnology has been  mainly focusing on solid tumors affecting adults. Not much attention is been made on childhood cancer in general and hematopoietic types per se. Two examples of preclinical studies have been discussed above and although they show promise in treatment and reduction of side effects, yet  additional research is needed to evaluated their effect in human clinical trials.

Ref:

1. The Genetic Origin of Childhood Acute Lymphoblastic Leukemia (ALL).  Reported by Aviva Lev-Ari, PhD, RN. March 20, 2013 https://pharmaceuticalintelligence.com/2013/03/20/the-genetic-origin-of-childhood-acute-lymphoblastic-leukemia-all/

2. Ching-Hon Pui, Leslie L Robison, A Thomas Look. Acute lymphoblastic leukaemia. Lancet 2008; 371: 1030–43.

http://www.med.upenn.edu/timm/documents/PuiLookLancetLeukemiareview.pdf

3. Wendy Stock. Adolescents and Young Adults with Acute Lymphoblastic Leukemia. Hematology December 4, 2010 vol. 2010 no. 1 21-29. http://asheducationbook.hematologylibrary.org/content/2010/1/21.full

4. Vinu Krishnan,  Xian Xu,, Sonali P. BarweXiaowei YangKirk CzymmekScott A. WaldmanRobert W. MasonXinqiao Jia, and Ayyappan K. Rajasekaran. Dexamethasone-Loaded Block Copolymer Nanoparticles Induce Leukemia Cell Death and Enhance Therapeutic Efficacy: A Novel Application in Pediatric Nanomedicine. Mol. Pharmaceutics 2012 ahead of print.

http://pubs.acs.org/doi/abs/10.1021/mp300350e?prevSearch=Rajasekaran&searchHistoryKey=

5. Uckun FMDibirdik IQazi SYiv S. Therapeutic nanoparticle constructs of a JAK3 tyrosine kinase inhibitor against human B-lineage ALL cells. Arzneimittelforschung 2010; 60(4): 210-217.

http://www.ncbi.nlm.nih.gov/pubmed/20486472

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