Adaptive Immunity and the Humoral and Cellular Response

Infectious disease occurs at the intersection of several critical factors:
- Pathogen characteristics
- Susceptible host biology
- Environmental factors
- The Immune System

Both T cells and B cells utilize complex receptor systems to identify antigens and communicate with other cells.
T Cell Receptors and Markers:
- Antigen-receptor complex: Composed of the T Cell Receptor ( $TCR$ ) and $CD3$ .
- Coreceptors: Includes $CD4$ or $CD8$ , which interact specifically with $MHC$ molecules.
- Complement Receptors: $CD35$ .
- Regulatory Receptors:
- Histamine receptors ( $H3$ ).
- Cytokine receptors: $CD25$ ( $IL-2$ receptor).
- Adhesion and Interaction Molecules: $CD2$ interacts with $CD58$ .
- Transport Receptors: $CD71$ (Transferrin receptor).
B Cell Receptors and Markers:
- Antigen-receptor complex: Composed of the B Cell Receptor ( $BCR$ ) and immunoglobulins such as $IgM$ .
- Complement Receptors: $CD21$ and $CD35$ .
- Immunoglobulin (Fc) Receptors:
- $CD32$ ( $Fc\gamma R$ ) for $IgG$ .
- $CD23$ ( $Fc\epsilon R$ ) for $IgE$ .
- $Fc\mu R$ for $IgM$ .
- Cytokine Receptors:
- $CD122$ and $CD25$ ( $IL-2$ receptors).
- $CD124$ ( $IL-4$ receptor).
- $CD125$ ( $IL-5$ receptor).

T cells possess a unique restriction: they can only recognize antigens when they are presented on a Major Histocompatibility Complex ( $MHC$ ) molecule.
Class I MHC:
- Found on regular (nucleated) cells.
- Presents antigens to $CD8^+$ T cells.
- Mnemonic/Note: Higher number is $1^{st}$ nerf or thi.
Class II MHC:
- Found on Professional Antigen-Presenting Cells ( $APCs$ ).
- Presents antigens to $CD4^+$ T cells.
- Mnemonic/Note: no g Lower number is $2^{nd}$ .

Activation of Naive T Cells:
- The initial activation of a naive T cell is always performed by a Dendritic Cell ( $DC$ ).
- The process involves:
1. Proliferation: The expansion of a specific T cell clone.
2. Differentiation: The development into effector cells or memory T cells.
Dendritic Cell Lifecycle:
- Immature $DCs$ encounter antigens within peripheral tissues.
- Following encounter, they migrate to lymphoid tissue and undergo maturation.
- Mature $DCs$ present the processed antigen in the lymph nodes to T cells.
T Cell Subsets and Differentiation:
- $CD4^+$ T cells: Differentiate into subsets like $Th1$ , $Th2$ , and $Th17$ . These cells express specific surface molecules and secrete cytokines to activate other immune cells.
- $CD8^+$ T cells: Differentiate into Cytotoxic T Lymphocytes ( $CTLs$ ) primarily responsible for killing infected cells.

$CD4^+$ $Th1$ cells:
- Function through cytokine secretion.
- Lead to the activation of macrophages.
- Promote the activation of $CD8^+$ Cytotoxic T Lymphocytes ( $CTLs$ ).
$CD8^+$ Cytotoxic T Lymphocytes ( $CTLs$ ):
- Function by inducing apoptosis in infected cells.

The humoral response is mediated by B cells and the antibodies they produce. Antigen recognition by B cells is not restricted by $MHC$ presentation.
B Cell Activation and Differentiation:
- A naive B cell (expressing $IgM^+$ and $IgD^+$ ) recognizes a microbe.
- Helper T cells and other stimuli trigger activation, leading to proliferation.
- Differentiation outcomes include:
- Antibody secretion: Development into plasma cells that secrete antibodies (initially $IgM$ ).
- Isotype switching: Transition from producing $IgM$ to other isotypes like $IgG$ , $IgA$ , or $IgE$ .
- Affinity maturation: Generation of high-affinity $Ig$ -expressing B cells (typically $IgG$ ).
- Memory B cells: Long-lived cells that persist to respond to future exposures.
Activation Pathways:
- T-dependent activation: Triggered by protein antigens involving follicular B cells and Helper T cells ( $Th$ ). Outcomes include isotype-switched, high-affinity antibodies, memory B cells, and long-lived plasma cells ( $IgG$ , $IgA$ , $IgE$ ).
- T-independent activation: Triggered by polysaccharide antigens, involving B-1 cells and marginal zone B cells. Other signals like complement proteins or microbial products are required. Outcomes are mainly $IgM$ , low-affinity antibodies, and short-lived plasma cells.

Immunoglobulins (antibodies) are categorized into classes or isotypes based on several criteria:
- Heavy chain structure.
- Molecular form (Monomeric vs. Polymeric).
- Subclasses.
- Serum concentration.
- Half-life ( $T_{1/2}$ ).
- Specific biological functions.
Effector Functions by Isotype:
- $IgG$ :
- Neutralization of microbes and toxins.
- Opsonization of antigens for phagocytosis by macrophages and neutrophils.
- Activation of the classical pathway of complement.
- Antibody-dependent cellular cytotoxicity ( $ADCC$ ) mediated by NK cells.
- Neonatal immunity: Transfer of maternal antibody across the placenta and gut.
- Feedback inhibition of B cell activation.
- $IgM$ :
- Activation of the classical pathway of complement.
- $IgA$ :
- Mucosal immunity: Secretion into the lumens of the gastrointestinal and respiratory tracts for neutralization of microbes and toxins.
- $IgE$ :
- Defense against helminths mediated by eosinophils and mast cells.
- Involvement in inflammation.
Distribution of Isotypes:
- $IgM$ : Located primarily in the blood.
- $IgG$ : Distributed in the blood and tissues.
- $IgA$ : Found on mucous membranes.
- $IgE$ : Found in epithelial tissue.

The kinetics of antibody production change upon repeated exposure to an antigen.
Primary Response:
- Occurs after the $1^{st}$ injection of antigen.
- Typically takes approximately $1$ to $2$ weeks for detectable levels.
- $IgM$ is the major antibody of primary responses.
Secondary Response:
- Occurs after the $2^{nd}$ injection of antigen.
- Characterized by a more rapid and robust increase in antibody titer.
- $IgG$ is the major antibody of secondary responses.