1. Macrophages (MΦ)
2. Mast cells
3. Basophils
4. Eosinophils
5. Neutrophils
6. Monocytes
7. B – Lymphocytes
   1. Plasma B-cells
   2. Memory B-cells
8. T – Lymphocytes (incl. Memory cells)
   1. Helper T-cells
   2. Cytotoxic T-cells
9. Natural Killer cells
10. Platelets
11. Other somatic cells

1. MHC I & II
2. Toll-like receptors (TLR)
3. Immunoglobulin complexes (IgD, IgM)
4. T-cell receptors (TCR)
5. F_c receptor (CD16)
6. Complement receptors (C3b, C3d)
7. CD4 (MHC-II receptor)
8. CD8 (MHC-I receptor)
9. Cytokine receptors

1. Blocking à barrier defenses
2. Holding à antibody – antigen complexes (A)
3. Devouring à phagocytosis (P)
4. Skewering à complement
5. Biting, scratching, kicking, punching à cytotoxic cells (C)
6. Headlock à inflammation (I)

1. Chemokines
   1. α - subgroup (IL-8): attract neutrophils
   2. β - subgroup (MIPs): attract macrophages
2. Interleukins
   1. IL-1: Early signal in specific immunity and inflammation; pyrogenic
   2. IL-2: From T_H à proliferation & activation of T_H, T_C, B-cells, NK cells
   3. IL-3: Hematopoiesis
   4. IL-4: T-cell and B-cell differentiation, B-cell class switching, promotes TH2
   5. IL-5: Eosinophil activation, B cell class switching
   6. IL-6: Growth of many cell types, incl. B-cells & T-cell; inflammatory response
   7. IL-10: Growth of B-cells, inhibition of TH1
   8. IL-12: TH1 & NK activation
   9. IL-17:  Neutrophil activation
3. Interferons
   1. IFN-a /b : Antiviral response; NK cell & macrophage activation, MHC expression
   2. IFN-g : Antiviral response, activation of many immune cells; response to LPS; IgG class switch; inhibition of TH2
4. Tumor Necrosis Factors
   1. TNF-a : LPS response: pyrogenic, IL-1,6 secretion, B-cell growth
5. Hematopoietins
6. Migration Inhibitory Factor (response to LPS, TNF-a , IFN-g )
7. Colony-Stimulating Factors

E. The Playbook

Play #2: Bacterial infection à T-dependent B-cell response

1. Macrophage or dendritic cell ingests bacterium
   1. Only DCs can initiate a first-time antigen-specific immune response
2. Activation of MΦ or iDC via TLR à cytokine release & maturation of iDC
   • APC produces IL-4, IL-12
3. Antigens combine w/ MHC-II of APC à cell surface
4. 1st Activation signal: T_H0 (CD4) cell recognizes MHC/Ag complex via its TCR & CD28/B7 costimulation
   • IL-12 stimulates TH0 à TH1 (local responses: inflammation, complement, IgG/IgM, macrophage activation)
   • IL-4 stimulates TH0 à TH2 (distant lymph nodes, late response)
   • IL-6 + TGF-b promotes TH0 à TH17 (local inflammatory, neutrophils)
   • IL-6 suppresses Treg cells
5. 2nd Activation signal: IL-1 from APC stimulates T_H proliferation

   Early/local Responses

6. Antigen binds to IgM & IgD on B-cells
   • LPS & C3d promote B-cell activation
   • B-cells secrete IgM
7. TH1 produce IL-2 & IFN-γ, which:
   • inhibits TH2 & further stimulates TH1
   • Class switching of B-cells to IgG
   • Activation of macrophages
   • inflammation
8. Mycobacterial/intracellular infections
   • Continual stimulation of TH1 by MΦ or DC bearing (mycobacterial) antigens on CD1 receptor
   • continued secretion of IFN-γ
   • Transformation of MΦ into epithelioid/giant cells à granuloma
   • CD1 activates NKT cells

   Late responses

9. T_H2 interacts with activated B-cells via CD4
   • T_H2 à IL-2 (and others) à B-cell differentiation (plasma cells) & proliferation
   • IL-4, 5, 6, 10 à IgG, IgA, IgE
10. Antibody production (10,000,000/hr)
11. Ab/Ag complexes may trigger NK response (see Play 4), complement response, or phagocytosis (opsonization)

    Termination of response

12. THreg cells (suppressor) à TGF-β à inhibits TH1 and TH2; differentiation of memory B & T cells

1. Virus infects cell à replication of viral proteins in cytosol
   • Infected cells produce interferons: antiviral response of nearby cells & NK activation; flu-like symptoms
   • Many infected cells produce IL-1 & TNF à fever, inflammation
2. Viral protein (antigen) combines with cytoplasmic MHC-I à targeted to membrane
3. Activated NK cells target virus-infected cells (abnormal MHC-I)
4. Macrophage/DC digests virus particles & presents viral antigens on its surface (MHC-II/Ag)
   • TLR on MΦ or DC further activate these via viral PAMPs
5. T_H0 cells recognize MHC-II/Ag (using CD4)
   • Activation is ‘confirmed’ using CD28 receptor
   • TH0 à TH1 (via IL-12)
6. TH1 can activate APC via TCR/Ag/MHC-II & costimulation by CD40L/CD40
   • APC can now activate TC directly via cross-presentation of antigen on MHC-I + CD28/B7 costimulation
7. MHC-I/Ag complex detected by T_C cell using CD8 receptor
8. T_H1 releases IL-2, IFN-g à T_C activation & proliferation
9. T_H1 and T_C release IFN and TNF à inhibit viral reproduction
10. T_C activates CD95 pathway (apoptosis) and releases perforin and granzymes
11. T_H2 may be involved (later) à recruit B-cells à antibodies
    • facilitates NK response (ADCC)

1. Tumor cell synthesizes new cell surface antigens
2. MHC-1 presents new antigens on cell surface
3. Activation of CD-8 Tc cells & cytolytic response (perforins & granzymes)
4. Soluble antigens generate a B-cell response à IgG secretion
5. IgG binds to antigens à coats cell surface
6. NK cell recognizes IgG via its CD16 (F_C) receptors
7. NK cell releases perforins and granzymes to destroy tumor cell

Play #5: Fungal infection

1. Antigen-presentation provokes TH1 response
2. TH1 produces IL-2 (inflammation) & IFN-g (activate macrophages)
3. Neutrophils, macrophages important for killing fungi

Play #6: Parasitic infection

1. Inflammatory response mediated by TH1 important for intracellular infections
2. TH2 responses important for extracellular protozoa and parasites
   • IgE activates mast cells & attracts eosinophils (anti-parasitic)
   • Histamine: mucus secretion, fluid secretion
   • IgA: mucosal protection

Play #7: Mycobacterium infection

1. Early: Inflammatory response important for mycobacterium (intracellular) infections
   • APC activates NKT cells (glycolipids via CD1) and metabolites activate γ/δ T-cell (tissue)
   • NKT and γ/δ T-cell produce IFN-y
2. MΦ secrete IL-12: TH0 à TH1 & production of IFN-y
3. TH17 cells promote inflammation early
4. IFN-y activated MΦ kill intracellular mycobacteria
5. large areas of necrosis become encapsulated with fibrin and become granulomas