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Complement And Immunoglobulin Biology Leading To Clinical Translation

Complement and immunoglobulins represent the two major arms of humoral immunity and are discussed in detail in respective major subsections of this chapter. The complement section begins with a comprehensive overview of pathway activation, regulation, and effector mechanisms, followed by discussion of the pathological consequences of various complement deficiencies and polymorphisms. Next discussed is complement’s integral role in B-cell and T-cell immunity. Additional topics include the…

B-Cell Development

B lymphocytes are the subset of white blood cells specialized to synthesize and secrete immunoglobulin (Ig). Their name derives from the finding that the avian b ursa of Fabricius is a site of B-cell production. However, post-natal B-cell production in mammals takes place in the bone marrow. Following their production, newly generated B lymphocytes migrate into secondary lymphoid organs such as the spleen where they undergo…

Natural Killer Cell Immunity AND THERAPY

Natural killer (NK) cells are large, granular lymphocytes that comprise about 10% to 15% of the circulating peripheral blood lymphoctyes. These unique cells were first characterized by their ability to lyse targets independently of activating or initiating stimuli. NK cells are a critical cellular component of the innate immune system that have the ability to target and lyse malignant and virally infected cells. In addition, NK…

Dendritic Cell Biology

Dendritic cells (DCs), originally discovered in 1973 by Ralph M. Steinman and Zanvil A. Cohn and named after their distinct stellate morphology, are important regulators of immune responses. Specialized in antigen acquisition, processing, and presentation, the hallmark of DCs is their ability to induce naïve T cell activation and effector differentiation. DCs also interact with other immune cells, such as B cells, natural killer (NK) cells,…

Aging and Hematopoiesis

Aging Increase in life expectancy has resulted in a major demographic global shift toward an elderly population. As a consequence, the prevalence of a multitude of age-associated diseases has increased gradually during the last decades, resulting in an increased number of hospitalizations of elderly individuals. A better understanding of the mechanisms that cause aging is crucial in order to mitigate age-associated clinical conditions. Multiple “hallmarks” of…

Cell Death

Core Apoptosis Pathways Apoptosis is a biochemically well-defined programmed cell death that is essential for normal development and cellular homeostasis; dysregulation of apoptosis is involved in several diseases. The classical morphological features of apoptosis include cell shrinkage, membrane blebbing, nuclear condensation, and deoxyribonucleic acid (DNA) fragmentation. The biochemical hallmarks of apoptosis include permeabilization of the outer mitochondrial membrane (MOMP), activation of caspases, and the externalization of…

Control of Cell Division

The Cell Division Cycle The mammalian cell cycle is divided into four phases: mitosis (M), deoxyribonucleic acid (DNA) synthesis (S), and the gap phases G1 and G2 ( Fig. 17.1 ). Mitosis is recognized when cells visibly undergo cell division and chromatin becomes condensed, sequentially progressing through prophase, metaphase, anaphase, and telophase. The G1 phase occurs immediately after mitosis has been completed and ends when DNA…

Current Biology of Stem Cell Homing and Mobilization: Dynamic Interactions Between Hematopoietic Stem and Progenitor Cells and Their Surrounding Bone Marrow Microenvironment

Introduction Hallmarks of hematopoietic stem and progenitor cell (HSPC) function include their dynamic metabolism, active bi-directional migration (bone marrow [BM] homing, egress, recruitment, and mobilization to the blood), durable multilineage BM and blood repopulation potential, self-renewal and chemotherapy resistance. Hematopoietic stem cells (HSCs) mainly reside in the BM, and their chemotherapy resistance requires their quiescence, adhesion, and metabolic interactions with bone-forming stromal cells. However, HSPCs are…

Cell Adhesion

Cell adhesion is essential for the development and maintenance of multicellular organisms. Cell-to-cell and cell-to-matrix adhesion provide a mechanism for intercellular communication and to define the three-dimensional architecture of organs. The regulated nature of cell adhesion is particularly evident in the hematopoietic system, where blood cells routinely make transitions between nonadherent and adherent phenotypes during differentiation, and in response to stimuli in the circulation or extravascular…

Hematopoietic Microenvironment

Evolution of the Niche Concept In 1868, Ernest Neumann first suggested that blood cells are being replenished throughout postnatal life, and this proposal led to the attempts to localize the place of hematopoiesis. His hypothesis that blood cell production takes place in the bone marrow (BM) was experimentally validated by selective lead shielding of limbs in irradiated animals almost a century later. Notably, these and other…

Stem Cell Model of Hematologic Diseases

Cell-Of-Origin Studies in Hematologic Malignancies One of the prevailing models of cancer development proposes that a cancer is initiated and maintained through the function of CSCs, which represent a rare population of cells within a cancer that have an indefinite proliferative potential and are ultimately responsible for the generation of the bulk of cancer cells. This so-called CSC hypothesis has been best studied in hematopoietic malignancies.…

Role of Chemokines in Leukocyte Trafficking

The mammalian immune system has evolved to mount multifaceted molecular and cellular microbicidal responses tailored and custom-adapted to eliminate an endless variety of infectious agents and, at the same time, remain tolerant to self-antigens. Accomplishing these tasks requires continuous tightly controlled movement of billions of motile immune cells that roam throughout the body along distinct nonrandom traffic routes from one tissue to another using blood and…

Cytokines, Chemokines, Other Growth Factors, and Their Receptors

Introduction Hematopoiesis is regulated by cytokine-cell and cell-cell interactions. Cytokines are polypeptides secreted by many cell types either constitutively or after induction and are usually classified based on primary structures associated with their receptor extracellular domains. They regulate a large range of biologic functions, including hematopoiesis, immunity, and inflammation. In context of hematopoiesis, they have effects on proliferation, differentiation, survival/cell death (apoptosis), and cell movement/migration/induced mobilization.…

Mitochondria and Hematopoiesis

Mitochondrial Structure and Function Mitochondria are very complex and highly dynamic organelles. Although responsible for only 10% of the cellular proteome, mitochondria serve not only as powerhouse of the cells but also as critical regulators of essential cellular processes including iron-sulfur cluster biosynthesis, calcium homeostasis, and cell death; hence they contribute to health and disease. Mitochondria are surrounded by a double-membrane system, consisting of an inner…

Hematopoietic Stem Cell Biology

Hematopoietic stem cells (HSCs) are characterized by their unique ability to self-renew and give rise to the entirety of the blood and immune system throughout the lifetime of an individual. HSCs are very rare cells, representing approximately one in 100,000 bone marrow (BM) cells in the adult. The concept of the existence of an HSC that is capable of reconstituting hematopoiesis in vivo was first introduced…

Pharmacogenomics and Hematologic Diseases

It is widely recognized that heritable genetic variation (i.e., genotypes or haplotypes) can translate into inherited phenotypes, some of which predispose to or cause diseases and others alter response to treatment. One aim of medical genetics and pharmacogenomics (PGx) is to understand the myriad associations between inherited genotypes and specific phenotypes of disease or drug response, with the ultimate goal of better defining the risk for,…

Protein Architecture: Relationship of Form and Function

Previous chapters outline the central dogma of mlecular biology: the storage of genetic information in DNA and its regulated transcription into messenger RNA and eventual translation into proteins. In this chapter, we briefly outline the chemical structure of proteins and their posttranslational modifications (PTMs). We explain how the properties of the 20 amino acids of which proteins are composed allow these polymers to fold into compact,…

Signaling Transduction and Metabolomics

Hematopoiesis is a cellular process in which self-renewing stem progenitor cells differentiate into mature blood cells, which carry out specific biologic functions. These functions include oxygen delivery, clot formation, and immune responses, including defense of the host from infection and inflammation. Homeostasis of the whole hematopoietic system in vivo requires a tight control of systems and networks governing proliferation, cell fate, cell death, differentiation, cell–cell interaction,…

Genome Editing

Genome editing is a rapidly developing field in which the genome of cells is modified with single nucleotide precision. This degree of precision is not achievable by other forms of genetic engineering, including contemporary lentiviral vectors, recombinases, or transposases. Not only is genome editing precise in the location of the changes made, but it is highly flexible and robust in the types of changes that can…

Regulation of Gene Expression in Hematology

Introduction The function of a cell is not only determined by the sum of the specific RNAs and proteins expressed but also by their metabolism, modification, and localization. To understand how a cell behaves, one must understand how the expression of genes, translation of transcripts, and processing of proteins are regulated. Through concerted regulation of these processes, hematopoietic stem cells (HSCs) maintain a balance between quiescence…