 Gram-positive cocci in chains  Hemolytic exotoxin  Capsule  Serogroup based on M antigen  Group A:  Pharyngitis  Scarlet fever  Necrotizing fascitis  TSS  Rheumatic fever  Glomerulonephritis  Increasing virulence? Streptococcus pyogenes

 Mucosal infection  Rapid variation in surface Ag  Ab/T-cells can cross-react with heart valve antigens  Colonization of multiple tissues Vaccine challenges

 Important in protection against disease  First contact for most pathogens  “Staging area” for many invasive pathogens  Mucosal vaccines  Oral polio vaccine (OPV)  Typhoid fever  Cholera  Rotavirus  Live attenuated flu vaccine (FluMist) Mucosal immunity

 Mucosa-associated lymphoid tissue (MALT)  Epithelium differentiates → FAE containing M cells  Expresses CCL20, CCL9  Follicles containing B and T cells (CCR6 +, CCR1 + ) MALT B cells T cells B cells T cells epithelium

 Mucosal epithelium  PAMP recognition, signaling by TLRs, etc.  Cytokines signal DCs and macrophages  Modulate reponse to avoid eliminating normal flora Antigen recognition

 DCs  Sample Ag transported by M cells  Migrate between cells to sample Ag directly  Carry Ag to adjacent T-cell zones and to lymph nodes Antigen recognition

 DCs present Ag to B and T cells Antigen recognition

 LPS, TGF  and IL-5 stimulate isotype switching to IgA  T-independent switching  Homing to MALT chemokines and adhesins Activation of T and B cells

 Inflammation, recruitment of phagocytes  IgG in lamina propria  ADCC  Activation of macrophages by T H  Killing by CTLs Effector mechanisms

 sIgA  Protease resistant  Transport by polymeric Ig receptor, pIgR  Entrapment in mucus (immune exclusion)  Transport back to lumen by pIgR  Neutralization (block colonization)  ADCC in lamina propria Effector mechanisms

 Systemic vaccines produce little mucosal immunity  Mucosal vaccines (nasal, oral, rectal, vaginal) primarily local  Nasal gives broadest response  Can induce Ab and CMI  May prime for later systemic vaccination Mucosal vaccines

 Ideal qualities:  Multimeric  Particulate  Adherent  PAMP Mucosal vaccines

 Immune response persists in absence of Ag  Long-term maintenance Memory

 Long-lived plasma cells (LLPCs)  Bone marrow  Constitutive Ab production  Isotype-switched, high-affinity Ab  No BCR  Terminally differentiated Humoral memory

 Memory B cells (MBC)  Lymph nodes  Do not produce Ab  High-affinity Ab receptor  Rapid recall response → plasma cells Humoral memory

 What’s the switch?  Both develop from germinal center B cells  CD40 stimulates differentiation into MBCs Humoral memory

 Longevity  LLPCs and MBCs have T ½ > 100 days  May persist for life  TLRs and CD40 may stimulate Ag-independent division  Maintenance  Re-exposure to pathogen (or booster vaccine)  Chronic or latent infection  Can persist in absence of Ag, but stimulation impaired  Ag stimulation required to retain full function? Humoral memory

 Maintenance  LLPCs and MBCs have T ½ > 100 days  Population can persist for life  Mechanisms:  Re-exposure to pathogen (or booster vaccine)  Chronic or latent infection  TLRs and CD40 stimulate Ag-independent division?  Can persist in absence of Ag, but stimulation impaired Humoral memory

 Response to re-infection  Neutralization by pre-existing Ab (from LLPCs)  Differentiation of MBCs into PCs (BCR stimulation)  Localized in Ag entry sites  More rapid differentiation (altered signal transduction) Humoral memory

 Development of memory T cells  Activated CTLs not long-lasting  Linear development of MTCs from CTLs? CMI memory

 Two major classes of memory cells  T CM - stem cells in lymph nodes  rapid differentiation in response to Ag  T EM - in tissues  less proliferation but more effector function CMI memory

 Maintenance  TLR activation  “Bystander” T H help  IL-15 (promotes division) & IL-7 (promtes survival) CMI memory