T and B Lymphocytes

• Immunity is either innate or adaptive
• Immune cells are lymphoid or myeloid

Lymphoid Cells

• Lymphoid cells include T cells, B cells, and NK cells
• Primary lymphoid organs are the bone marrow (BM) and thymus
• Secondary lymphoid organs are lymph nodes and the spleen
• Lymphoid aggregators include Peyer's patches or tonsils

T-Lymphocytes

• T-lymphocytes are derived from the thymus
• T-lymphocytes represent 75-80% of blood lymphocytes
• Function: cell-mediated immunity
• Markers include TCR, CD3, CD4 & CD8

Types of T-Lymphocytes

• T-helper (CD4+) cells help B-cells and macrophages
• Cytotoxic (CD8+) cells kill tumor and virus cells
• T-regulatory cells suppress immunity
• Recognition is by TCR and only peptide + MHC

B-Lymphocytes

• B-lymphocytes are derived from BM
• B-lymphocytes represent 10-15% of blood lymphocytes
• Markers include surface Ig, CD19, CD21, and class MHC II
• Function: Humoral immunity
• Recognize antigen (Ag) by BCR
• Make antibody (Ab) or memory cells

NK Cells

• NK cells represent 10% and are part of the innate immunity
• Marker: CD16
• Function: Kill tumor and virus cells
• Make IFN-γ

Types of NK Cell receptors

• KARs and KIRs
• KARs and KIRs inhibit if binds sufficiently to MHC I

Stem Cells

• Stem cells are unspecialized cells
• Stem cells have self-renewal ability and potency (ability to become any cell)

Types of Stem Cells

• Embryonic stem cells (inner cell mass of blastocyst)
• Adult stem cells (adult tissues)

Potential Treatments Using Stem Cells

• Cardiovascular repair (heart)
• Spinal cord repair (regrowing neurons)
• Alzheimer's disease (replacing damaged brain cells)
• Muscle damage
• Type I DM (replace pancreatic beta cells)
• Leukemia (transplant bone marrow)

Antigen-Presenting Cells (APCs)

• Types of APCs include dendritic cells, macrophages, and B-lymphocytes
• Occurrence of APCs: skin, respiratory tract, and GIT tract

Functions of APCs

• Capture & transport antigen (Ag) to lymphoid tissues
• Process antigen (Ag)
• Present peptides to T-cells

Types of Antigen Presentation

• Class II: extracellular, lysosomal proteases, present to CD4+ T cells
• Class I: intracellular, proteasome, present to CD8+ T cells

Phagocytes

• Phagocytes are cells that recognize, ingest, & kill microbes

Types of Phagocytes

• Monocytes: large mononuclear cells in blood
• Macrophages: monocytes in tissues
• Neutrophils: most abundant leukocyte that kills bacteria

Phagocytosis

• Delivery of phagocytic cells involves diapedesis (histamine helps) & chemotaxis (C5a, chemokines)
• Recognition of microbes: by mannose & toll-like receptors
• Adherence (opsonization): enhanced by opsonins (IgG & C3b)
• Ingestion: phagosome forms
• Phagolysosome: phagosome + lysosome
• Intracellular killing: O2 dependent (toxic nitrogen oxide, O2, OH, H2O2) and O2 independent mechanisms
• Lysosomal granules damage permeability barrier
• Lysosomal enzymes include lysozyme & nucleases
• Lactoferrin binds iron, inhibiting growth
• Low pH prevents growth
• Digestion: neutrophils are short lived & lyse itself & forms pus
• Macrophages egest debris

Antigens

• Antigens are recognized by the immune system
• Characteristics: simple or complex
• Include carbohydrates, lipids, proteins, nucleic acids, and phospholipids
• Have epitopes (antigenic determinants) and may be multivalent (more than one)

Types of Antigens (According to Response)

• Immunogens: large, bind to receptor, and induce a response
• Haptens: small, bind and induce only if bound to a large molecule
• Toleragens: no stimulation

Types of Antigens (According to T-cell Need)

• T-cell independent: B cells work alone (e.g., polysaccharide)
• T-cell dependent: require T cell help (e.g., protein)

Factors Affecting Immunogenicity

• Size (protein > lipids)
• Complexity (numerous diverse epitopes)
• Conformation & accessibility
• Chemical properties (protein is good, lipids/carbs/steroids are poor, amino acids/haptens are not immunogenic)

Immunoglobulins (Antibodies)

• Glycoproteins that mediate humoral immunity
• Produced in lymph nodes by B-cells

Types of Immunoglobulins

• Membrane-bound (IgM & IgD)
• Secreted (Ig) in plasma, mucosa, interstitial fluids (IgA is this type)

Structure of Immunoglobulins

• Y-shaped with 4 chains (2 heavy & 2 light)
• Heavy chain = 1 variable (VH) & 3-4 constant (CH) domains
• Light chain = 1 variable (VL) & 1 constant (CL) domain
• Chains connected by disulfide bonds
• Variable regions have 3 hypervariable regions called CDRs

Regions of Antibodies (Ab)

• Fab [fragment binding] = 2 in number (light, VH, CH)
• Fc [crystalline/effector biological function] = 1 (the remaining CH)
• Hinge region connects Fab & Fc and gives them mobility

Types of Antibodies

• Monoclonal Ab: clones from a single parent (monospecific)
• Polyclonal Ab: derived from an immunized host
• Hybridoma: B-cells with myeloma cells; secrete large amounts of monoclonal antibodies (mAbs)

Uses of Antibodies

• Identify phenotype markers
• Immuno diagnosis
• Tumor diagnosis
• Therapy (e.g. Anti-CD3)

Antibody Isotypes

• IgA: subtypes IgA1 and IgA2, a1 or a2 H chain, serum 3.5 mg/ml, secreted as monomer/dimer/trimer, mucosal immunity, protects to surface diseases.
• IgD: δ H chain, traces of serum, not secreted, B cell receptor.
• IgE: ε H chain, 0.05 mg/ml serum, secreted as monomer, parasite immunity, allergy.
• IgG: subtypes IgG1-4, γ H chain, 13.5 mg/ml serum, secreted as monomer, opsonization, complement activation, ADCC.
• IgM: μ H chain, 1.5 mg/ml serum, secreted as pentamer, B cell receptor, complement activation.
• IgG is the most abundant immunoglobulin isotype.

Adaptive Immunity

• Humoral (antibodies)
• Extracellular mediated by Ab
• Cell mediated
• Intracellular

Humoral Immunity (Antibody Isotype Functions)

• Neutralization of microbes & toxins
• Prevents binding of microbes to cells and toxins to receptors
• Opsonization & phagocytosis: opsonins (IgG & C3b) promote phage cytosis
• ADCC: IgG binds to cell by Fab and to NK with Fc → kill the cell
• IgE → bind to parasite by Fab and to eosinophils with Fc → release granule content → kill parasite
• Complement activation: IgG & IgM
• Special sites: IgA = mucosal, IgG = neonatal

Cell-Mediated Immunity

• T-helper cells
• TH1: works by IL-12 → secret IFN-γ → activate phagocytes
• TH2: IL-4 → Secrete IL-4,65 → degrade mast & Eosinophils
• CD8+ T-cells
• 1st signal: (MHC + peptide on TCR-CD3)
• 2nd signal: (B7 on APC with CD28)
• If no 2nd signal: = Anergy

Steps of CD8+ T cell Killing

• Recognize signal
• Form tight adhesions with the target
• IL-2 & IFN-γ stimulate CTLs to release granule content
• Perforin (form pores in cell membrane)
• Granzyme (enter & stimulate apoptosis)
• Detachment of CTL
• The cell dies

MHC

• MHC is located on the short arm of chromosome 6.
• Class I: 2 chains: α1, α2, α3 (groove) & β2
• Class II: 2 chains: α1, α2 & β1, β2 groove

Primary vs Secondary Immune Response

• Primary Response: slow in onset, low in magnitude, short lived, IgM
• Secondary Response: rapid in onset, high in magnitude, long lived, IgG (or IgA, or IgE)