cell mediated responses

Characteristics of Adaptive (Specific) Immunity

Adaptive immunity represents the third line of defense and is defined by the body's ability to recognize and defend itself against distinct invaders and their products. It possesses several hallmark characteristics:

• Specificity: Unlike the innate immune system, adaptive immunity targets specific pathogens.

• Inducibility: Cells of the adaptive immune system activate only in response to specific pathogens.

• Memory: The system responds to pathogens it has previously encountered, allowing for faster and stronger subsequent reactions.

• Self-tolerance: The system does not respond against normal body cells or the microbiome.

Lymphocytes Involved in Adaptive Immunity

Adaptive immunity is primarily driven by two types of lymphocytes:

• B Lymphocytes (B cells): These cells mature in the bone marrow and are primarily found in the spleen and the primary follicles of lymph nodes, with a small amount circulating in the blood. Their main function is to secrete soluble antibodies (immunoglobulins) specific to a particular villain or a specific epitope.

• T Lymphocytes (T cells): These cells originate in the bone marrow but mature in the thymus under the influence of molecular signals. They account for $75-85\%$ of all lymphocytes in the blood and later migrate to the lymph nodes and spleen. T cells act as orchestrators for both innate and adaptive responses and are responsible for destroying cells infected with pathogens or cancers. They utilize T-cell receptors (TCRs) for specific antigen binding.

Functional Classification of T-Lymphocytes

T-cell types are distinguished by their surface glycoproteins and specific functions:

• Cytotoxic T Cells (CD8^+ T Cells): These cells directly attack and destroy infected or cancerous cells. They recognize antigens presented by MHC Class I molecules and release perforins and granzymes to induce apoptosis in target cells.

• Helper T Cells (CD4^+ T Cells): These cells coordinate immune responses by activating other immune cells, including B cells for antibody production and cytotoxic T cells. They recognize antigens presented by MHC Class II molecules and release cytokines to enhance the immune response.

• Regulatory T Cells (Tregs): These cells maintain immune homeostasis by suppressing excessive immune responses and preventing autoimmunity. They modulate other T cell activities to prevent inflammation and tissue damage.

The Major Histocompatibility Complex (MHC)

The MHC is a group of genes located on chromosome 6 in humans, referred to as Human Leukocyte Antigens (HLA). These genes encode proteins essential for distinguishing self from non-self by presenting antigens to T cells. MHC compatibility is critical for organ-grafting; mismatched HLA types result in organ rejection.

MHC Classes

• MHC Class I:     - Location: Found on the surface of all nucleated cells.     - Function: Present endogenous (intracellular) antigens, such as viral proteins, to $CD8^+$ cytotoxic T cells.     - Mechanism: If a cell is infected, viral peptides are processed by the proteasome, loaded onto MHC I in the endoplasmic reticulum, and presented on the cell surface to trigger destruction by T cells.

• MHC Class II:     - Location: Found only on "professional" antigen-presenting cells (APCs) such as monocytes (dendritic cells and macrophages), epithelial cells, and B cells.     - Function: Present exogenous (extracellular) antigens to $CD4^+$ helper T cells.     - Mechanism: A macrophage engulfs a bacterium (e.g., Mycobacterium tuberculosis), processes the peptides in a phagolysosome, and loads them onto MHC II for presentation to helper T cells to activate the broader immune response.

Antigen Presentation and Pathways

Adaptive immune responses are initiated in the lymphoid organs rather than at the site of infection. Antigen presentation involves capturing, processing, and displaying antigens to T cells.

• Exogenous Pathway (MHC-II): This pathway involves professional APCs (dendritic cells, macrophages, B cells) dealing with extracellular pathogens (bacteria, toxins). Antigens are engulfed, processed, and presented to $CD4^+$ helper T cells.

• Endogenous Pathway (MHC-I): This occurs in all nucleated cells dealing with intracellular pathogens (viruses). Antigens are degraded in the proteasome, loaded onto MHC I, and presented to $CD8^+$ cytotoxic T cells to induce cell death.

Clonal Deletion and Self-Tolerance

Because TCRs and BCRs (B-cell receptors) are generated randomly, the body must eliminate cells that react against "autoantigens" to prevent autoimmune diseases.

T-cell Clonal Selection in the Thymus

Young T lymphocytes spend approximately one week in the thymus being exposed to natural epitopes (e.g., lysozyme, hemoglobin, muscle proteins). They face four potential fates:

1. Positive Selection: T-cells that moderately recognize self-MHC molecules receive survival signals.

2. Negative Selection: T-cells that bind too strongly to self-antigens undergo apoptosis. T-cells that fail to recognize MHC molecules at all also undergo apoptosis.

3. Regulatory T-cell Differentiation: Some self-reactive T-cells become Tregs to help suppress immune responses.

4. Periphery Migration: Functional T-cells that recognize foreign antigens exit to the lymphatic circulation.

B-cell Clonal Deletion in the Bone Marrow

1. Apoptosis (Clonal Deletion): Immature B-cells that bind strongly to self-antigens are destroyed.

2. Receptor Editing: Some self-reactive B-cells modify their BCR genes to eliminate self-reactivity.

3. Anergy: B-cells that bind weakly to self-antigens become functionally inactive.

4. Maturation: Successful B-cells survive and migrate to peripheral lymphoid organs.

Overview of Adaptive Immune Responses

Anatomy of the System

• Primary Organs/Tissues: Bone marrow, thymus, and bursa of Fabricius.

• Secondary Organs/Tissues: Spleen and lymph nodes.

• Cell Lineages: Lymphocytes (B and T), Monocytes/Macrophages, and Granulocytes (neutrophils, basophils, eosinophils).

Antibody-Mediated (Humoral) Immunity (AMI)

AMI is mediated by antibodies in plasma, lymph, and tissue fluids. It targets extracellular microbes and toxins.

• Mechanism: B cells recognize antigens via BCRs, process them, and display them on MHC II to activated helper T cells. These T cells release lymphokines that cause the B cells to differentiate into plasma cells, which secrete soluble antibodies.

• Effector Mechanism: Antibodies coat virus particles to prevent fusion with host membranes and mark them for phagocytosis by macrophages.

Cell-Mediated Immunity (CMI)

CMI uses direct cell-to-cell contact or cytokine stimulation to respond to intracellular antigens.

• Requirements: Recognition of foreign antigens by T cells, activation via APCs, removal of antigens (phagocytosis/neutralization), return to homeostasis (via Tregs and cytokines), and maintenance of memory.

Immune Memory and Response Phases

Memory is the foundation of vaccination and prevents reinfection through long-lived memory B cells, memory T cells, and long-lived plasma cells.

Primary vs. Secondary Responses

• Primary Response: Triggered by the first exposure to an antigen. It is slow (taking days to weeks) as it involves clonal selection and the expansion of naive B and T cells. It results in the formation of effector cells and a reservoir of memory cells.

• Secondary Response: Triggered by subsequent exposure to the same antigen. This response is much faster and stronger. Memory B cells rapidly differentiate into plasma cells to produce high-affinity antibodies. Memory T cells (including central memory in lymph nodes and effector memory in tissues) quickly reactivate to clear pathogens, often preventing clinical symptoms.

Anatomical Distribution of Phagocytes

• Brain: Microglial cells

• Joints: Synovial A cells

• Bone Marrow: Precursors

• Lymph Nodes: Resident and recirculating macrophages

• Blood: Monocytes

• Kidney: Mesangial phagocytes

• Spleen: Macrophages

• Liver: Kupffer cells

• Lung: Alveolar macrophages