Chapter 2

Phagocytes

Phagocytes, including neutrophils and macrophages, are cells whose primary function is to identify, ingest, and destroy microbes

In host defense consist of sequential steps: recruitment of the cells to the sites of infection, recognition of and activation by microbes, ingestion of the microbes by the process of phagocytosis, and destruction of ingested microbes

Neutrophils Polymorphonuclear leukocytes (PMN), nucleus with three to five connected lobules

most abundant population of circulating WBC

12 to 15µm

The cytoplasm contains granules of two types, specific granules (enzyme such as lysozyme, collagenase, and elastase) that do not stain strongly with either basic or acidic dyes and azurophilic granules (lysosomes containing enzymes and other microbicidal substances, including defensins and cathelicidins)

Production of neutrophils is stimulated by granulocyte colony-stimulating factor (G-CSF)

An adult human produces more than 1 x 1011 neutrophils per day

function for a few hours (6h) and then die

Mononuclear Phagocytes (MMN)

Play central roles in innate and adaptive immunity

Unlike neutrophils, macrophages are not terminally differentiated and can division at an inflammatory site

Incompletely differentiated and is called monocyte

Some develop abundant cytoplasm and are called epithelioid cells

Later stages of the innate immune response, 1 or 2 days after infection

Macrophages in different tissues, microglial cells (CNS), Kupffer cells (liver), alveolar macrophages (pulmoner); osteoclast(bone)

Maturation of MMN and Dendritic Cells

Several important functions in innate and adaptive immunity: A major function of macrophages in host defense is to ingest and kill microbes ingest dead host cells as part of the cleaning up process after infection or sterile tissue injury Activated macrophages secrete proteins, called cytokines, Macrophages serve as APCs promote repair of damaged tissues by stimulating new blood vessel growth (angiogenesis)

and synthesis of collagen-rich extracellular matrix (fibrosis)

Macrophages are activated to perform their functions by recognizing many different kinds of microbial molecules as well as host molecules produced in response to infections (Toll-like receptors)

Macrophages can acquire distinct functional capabilities, depending on the types of activating stimuli

Some of these cytokines activate macrophages to become efficient at killing microbes, called classical activation

Other cytokines activate macrophages to promote tissue remodeling and repair, called alternative activation

Macrophage-like cells (hemocytes) are phylogenetically the oldest mediators of innate immunity

Mast Cells

Mast cells are bone marrow–derived cells that are present in the skin and mucosal epithelium and contain abundant cytoplasmic granules filled with cytokines, histamine, and other mediators

Stem cell factor (also called c-Kit ligand) is a cytokine that is essential for mast cell development

Express plasma membrane receptors for IgE and IgG antibodies

Provide defense against helminths but are also responsible for symptoms of allergic diseases

Basophils

Basophils are blood granulocytes with many structural and functional similarities to mast cells

less than 1% of blood leukocytes

Normally not present in tissues, basophils may be recruited to some inflammatory sites

Importance in host defense and allergic reactions is uncertain

Eosinophils

Blood granulocytes express cytoplasmic granules containing enzymes that are harmful to the cell walls of parasites but can also damage host tissues

GM-CSF, IL-3, and IL-5 promote eosinophil maturation from myeloid precursors

Antigen-Presenting Cells (APC)

Specialized to capture microbial, display them to lymphocytes, and provide signals to stimulate the proliferation and differentiation of lymphocytes

Major type of APC that is involved in initiating T cell responses is the dendritic cell (DC)

Macrophages present antigens to T cells during CMI responses, and B lymphocytes function as APCs for helper T cells during humoral immune responses

A specialized cell type called the follicular dendritic cell (FDC) displays antigens to B lymphocytes during particular phases of humoral immune responses

APCs link responses of innate immune system to responses of the adaptive immune system,

Dendritic Cells

Play important roles in innate immunity to microbes and in antigen capture and the induction of T lymphocyte responses to protein antigens

Arise from bone marrow precursors, mostly of the monocyte lineage, and are found in many organs

Activated DC also express molecule called costimulators, which function in concert with antigen to stimulate T cells

Follicular Dendritic Cells (FDC)

Are present involve in specialized collections of activated B cells, called germinal centers

Are not derived from precursors in the bone marrow and are unrelated to the dendritic cells

FDCs trap antigen-antibodies complexes to or complement products for recognition by B lymphocytes

Important for the selection of activated B lymphocytes

Lymohocytes Lymphocytes are the only cells in the body capable of specifically

recognizing and distinguishing different antigenic determinants and are responsible for the two defining characteristics of the adaptive immune response, specificity and memory

Major subsets of B cells (B2 cell) are follicular B cells, marginal zone B cells, and B1 cells,

T cell subsets are helper T lymphocytes (Th CD4+), cytotoxic T lymphocytes (CTLs), which express an antigen receptor called the αβ receptor, CD4+ regulatory T cells , and γδ T cells

NKT cells are a numerically small population of lymphocytes that share characteristic of both NK cells and T cells

Maturation of Lymphocytes

Naive Lymphocytes

Are mature T or B cell emigrants from generative lymphoid organs that have never encountered foreign antigen

Die after 1 to 3 months, if they do not recognize antigens

Naive and memory lymphocytes, are both called resting lymphocytes, because they are not actively dividing, nor are performing effector functions

Effector Cells

Include helper T cells, CTLs, and antibody secreting B cells

Majority of differentiated effector T lymphocytes are short lived and not self- renewing

Many antibody-secreting B cells are morphologically identifiable as plasma cells

Morphology of Plasma Cells

Memory Cells

Identified by their expression of surface proteins although it is still not clear which definitive markers of memory populations

Memory B lymphocytes express certain classes of membrane Ig, such as IgG, IgE, or IgA, whereas naive B cells express only IgM and IgD

In humans, CD27 expression is a good marker for memory B cells

In humans, most naive T cells express a 200-kD isoform of a surface molecule called CD45RA (for restricted A)

In contrast, most activated and memory T cells express a 180-kD isoform of CD45RO

Small lymphocyte Large lymphocyte

The Anatomy of Lymphocyte Activation

ANATOMY AND FUNCTIONS OF LYMPHOID TISSUES

Lymphoid tissues are classified as generative organs or primary lymphoid organs (Thymus and BM), where lymphocytes first express antigen receptors and attain phenotypic and functional maturity, and as peripheral organs or secondary lymphoid organs (LN, spleen,…) where lymphocyte responses to foreign antigens are initiated and develop

Bone Marrow Is the site of generation of all circulating blood cells in the adult

During fetal development, the generation of all blood cells, called hematopoiesis

Stem cells express two proteins called CD34 and stem cell antigen 1(Sca-1)

Proliferation and maturation of precursor cells in the bone marrow are stimulated by cytokines are called colony-stimulating factors

Hematopoiesis (Hematopoietic Tree)

Thymus

Is the site of T cell maturation

Is a bilobed organ situated in the anterior mediastinum. Each lobe is divided into multiple lobules by fibrous septa, and each lobule consists of an outer cortex and an inner medulla

Cortex contains a dense collection of T lymphocytes

Scattered throughout the thymus are nonlymphoid epithelial cells, which have abundant cytoplasm

Hassall's corpuscles, which are composed of tightly packed whorls of epithelial cells that may be remnants of degenerating cells

Thymus In general, the most immature cells of the T cell lineage enter the thymic

cortex through the blood vessels. Maturation begins in the cortex, and as thymocytes mature, they migrate toward the medulla, so that the medulla contains mostly mature T cells

Morphology of Lymph Node

Lymph Nodes and Lymphatic System

Dendritic cells capture some microbial antigens and enter lymphatic vessels

Adaptive immune responses to antigens that enter through epithelia or are found in tissues are initiated in lymph nodes

Some of the lymph from the subcapsular sinus is channeled through specialized conduits that run through the paracortical T cell zone toward specialized vessels called high endothelial venules (HEV)

Lymph node consists of an outer cortex and an inner medulla. Outer cortex contains primary (without GC) and secondary (with GC) follicles with germinal center

Follicles are B cell zones of lymph nodes

Primary follicles contain mostly mature, naive B lymphocytes

Germinal centers develop in response to antigenic stimulation. They are sites of remarkable B cell proliferation, selection of B cells producing high-affinity antibodies, and generation of memory B cells

Each lymphocyte population is in close contact with the appropriate APCs (T cells with dendritic cells and B cells with FDCs)

Microanatomy of Lymph node Cortex

Morphology of the Spleen

Spleen

Lymphocyte-rich regions of the spleen, called the white pulp, are organized around branches of these arteries, called central arteries

White pulp is segregated T cell and B cell zones

Central arteries are surrounded by cuffs of lymphocytes, most of which are T cells that morphologists call these areas periarteriolar lymphoid sheaths

Marginal zone is populated by B cells (MZ B cells) and specialized macrophages

Spleen is also an important filter with phagocytosis for the blood (red pulp)