Comprehensive Study Notes on the Immune System and Lymphoid Biology

Overview of Immunity and the Immune System

Immunity is defined as the inherent ability of an organism to resist infections caused by pathogens. The immune system is a complex network consisting of various organs, specialized cells, and specific molecules that work in concert to protect the body. This system is fundamentally divided into two major components: the innate (natural) immune system and the adaptive (acquired) immune system.

The innate immune system represents the body's first and second lines of defense. It is considered non-specific. The first line of defense consists of external barriers, while the second line involves internal mechanisms. In contrast, the adaptive immune system is specific to particular antigens and is further subdivided into humoral immunity and cellular immunity. Humoral immunity is mediated by antibodies produced by B cells, whereas cellular immunity is mediated by T cells.

Anatomical Organization of Lymphoid Organs

The organs of the immune system are categorized into primary and secondary lymphoid organs based on their functional roles in the development and activation of immune cells. Primary (1ry) or central lymphoid organs are the sites where immune cells are produced and undergo maturation. These include the Bone Marrow and the Thymus. The bone marrow is the site of origin for all immune cells and the maturation site for B cells, while the thymus is the site where T cells mature.

Secondary (2ry) or peripheral lymphoid organs are the sites where adaptive immune responses are initiated as these organs capture antigens and bring them into contact with mature lymphocytes. These include the Lymph nodes, which serve to collect antigens (Ag) from sites of infection within the tissues; the Spleen, which is responsible for collecting antigens circulating in the blood; and the Mucosa-Associated Lymphoid Tissues (MALT). MALT is specifically found in the gastrointestinal and respiratory tracts, serving as a localized defense mechanism for mucosal surfaces.

Hematopoiesis and the Lineages of Immune Cells

All cells of the immune system arise from pluripotent stem cells. During embryonic development, these stem cells are found in the yolk sac and the liver. In adults, hematopoiesis occurs primarily in the bone marrow. Stem cells differentiate into two main progenitor lineages: the lymphoid stem cell and the myeloid stem cell.

The lymphoid stem cell lineage gives rise to lymphocytes, which include B cells, T cells, and Natural Killer (NK) cells. The myeloid stem cell lineage differentiates into various other cell types, including granulocytes (neutrophils, eosinophils, basophils, and mast cells), monocytes (which further differentiate into macrophages), and dendritic cells.

Characteristics and Functions of B Lymphocytes

B cells develop and mature in the Bone Marrow. They constitute approximately $30\%$ of the peripheral lymphocytes and generally have a short life span ranging from days to weeks. The primary function of B cells is humoral mediated immunity, achieved through the secretion of antibodies (Abs) that are specific to a particular antigen (Ag). B cells express a specific surface receptor known as the B cell receptor (BCR), which consists of monomeric $IgM$ and sometimes $IgD$, as well as the $CD40$ marker.

The Clonal Selection Theory explains how the body responds to specific antigens. Each B cell expresses a surface-specific receptor for only one antigen. When a specific antigen enters the body, it "selects" the B cell that carries the corresponding immunoglobulin receptor. This interaction between the antigen and the BCR leads to proliferation, also known as clonal expansion, and subsequent differentiation. The B cells differentiate into plasma cells, which secrete five different types of antibodies ($IgG$, $IgD$, $IgE$, $IgA$, and $IgM$) to act against the antigen, and memory cells, which provide long-term immunity.

Characteristics and Functions of T Lymphocytes

T cells develop in the bone marrow but migrate to the Thymus for maturation. They represent $65-80\%$ of peripheral lymphocytes and possess a long life span, often lasting for months or years. T cells are central to cell-mediated immunity and specialize in distinguishing self from non-self antigens. The T cell receptor (TCR) is used for antigen binding, and these cells also express markers such as $CD3$ and $CD28$.

T cells are categorized into two primary types based on their surface markers. T-helper (Th) cells express the $CD4$ marker and make up roughly $65\%$ of the T cell population. They act as the orchestrators of the immune response. Naïve T-helper cells ($Th0$) can be converted into either $Th1$ or $Th2$ cells upon stimulation. Another subtype, regulatory T cells ($Treg$), which express $CD25$, function to stop the immune reaction once it is no longer needed. Activated Th cells also present the $CD40L$ ligand. T-cytotoxic (Tc) cells express the $CD8$ marker and comprise about $35\%$ of T cells. Their role is to kill intracellular organisms, such as virus-infected cells, as well as abnormal cells like tumor cells and graft cells. The normal ratio of $Th : Tc$ in the body is approximately $2 : 1$.

Functional interaction involves $CD8$ T cells recognizing peptides presented on $MHC$ class I molecules to become cytotoxic T cells (CTL) that kill target cells. $CD4$ T cells recognize peptides on $MHC$ class II molecules. $TH1$ cells typically activate macrophages to destroy intracellular bacteria, while $TH2$ cells activate antigen-specific B cells to differentiate into plasma cells (B lymphoblasts) that produce anti-toxin antibodies.

Natural Killer (NK) Cells

Natural Killer cells develop from lymphoid stem cells and represent $5-10\%$ of peripheral lymphocytes. They are unique because they can kill target cells without the need for prior activation or antigen presentation. Their membranes feature important receptors, including $CD56$ and $CD16$ (a receptor for the Fc portion of $IgG$). They also possess Killer Activation Receptors (KAR) used to identify and kill virally infected or tumor cells, and Killer Inhibition Receptors (KIR). KIRs prevent the killing of normal cells by assessing the presence of $MHC$ I molecules; if $MHC$ I is present on a normal cell, the KIR provides an inhibitory signal.

NK cells serve several functions. In innate immunity, they perform cytolysis on infected or cancerous cells. This mechanism is similar to that of Tc cells, utilizing perforins and granzymes, but it is non-specific and $MHC$-unrestricted. In acquired immunity, NK cells participate in Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) by binding to $IgG$-coated cells. Additionally, they produce cytokines such as $IFN-\gamma$ and $TNF-\alpha$. If NK cells are activated by $IL-2$, they are termed Lymphokine Activated Killer (LAK) cells, which possess increased killing efficiency and are utilized in cancer therapy.

Myeloid Lineage: Granulocytes

Granulocytes develop from myeloid stem cells and are characterized by segmented nuclei and cytoplasmic granules visible with special stains. This group includes neutrophils, eosinophils, basophils, and mast cells. Neutrophils are polymorphonuclear phagocytic cells and are typically the first cells recruited to a site of infection. They migrate through the blood stream using processes such as tethering, rolling, adhesion, and transendothelial migration (penetrating the basement membrane to reach tissues).

Eosinophils play a critical role against parasitic infections and also possess phagocytic functions. They interact with parasites using receptors for the Fc portion of $IgE$ or $IgG$. Basophils are non-phagocytic cells that possess receptors for $IgE$ and release histamine. Mast cells are functionally similar to basophils but are not found in the blood; instead, they reside in tissues in close contact with the external environment, such as the skin, airways, and intestines. When an allergen cross-links $IgE$ bound to the surface of a mast cell, mediators like histamine are released.

Monocytes and Macrophages

Macrophages are mononuclear phagocytes that develop from myeloid stem cells. While circulating in the blood, they are called monocytes; once they migrate into tissues, they are termed macrophages and are given specific names based on their location: Microglial cells in the Central Nervous System (CNS), Kupffer cells in the liver, Alveolar macrophages in the lungs, and Osteoclasts in the bone. They express important receptors including $MHC$ class I, $MHC$ class II, receptors for the Fc portion of $IgG$, and receptors for the $C3b$ complement component.

Macrophages perform four main functions: phagocytosis, antigen presentation, cytokine production, and complement synthesis. Phagocytosis can be oxygen-dependent or oxygen-independent and can occur directly or indirectly. Indirect phagocytosis involves opsonization, where pathogens are coated with opsonins like $IgG$ or $C3b$ to facilitate ingestion by the phagocyte. As Professional Antigen-Presenting Cells (APCs), macrophages process and present antigens to T lymphocytes using $MHC$ Class II. They also produce essential cytokines, including $IL-1$, $IL-6$, $IL-12$, and $TNF-\alpha$.

Dendritic Cells

Dendritic cells also develop from myeloid stem cells. Their physical structure is characterized by elongated projections that resemble neuronal dendrites. They express high levels of $MHC$ II on their surface. The primary and most significant function of dendritic cells is to act as professional Antigen-Presenting Cells (APCs), playing a vital role in the activation of the adaptive immune response.