Human M. tuberculosis infection/ disease: classical pathology and

immunology (Slide -1)

Human M. tuberculosis infection/ disease: classical pathology and

immunology (Slide -1)

W. Henry Boom, M.D.

Tuberculosis Research Unit (TBRU)

Case Western Reserve University

W. Henry Boom, M.D.

Tuberculosis Research Unit (TBRU)

Case Western Reserve University

NIAID-DMID: -AI70022

Cattle Prod 1950

Route(s) of Infection & Natural Course (Slide 0)

Route(s) of Infection & Natural Course (Slide 0)

• small vs. large droplet aerosol

• repeated exposure

• ?infectious dose (animals: 1-10 CFU)

• ?repeated infection

• small vs. large droplet aerosol

• repeated exposure

• ?infectious dose (animals: 1-10 CFU)

• ?repeated infection

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IO PROGRESSIVE: PEDS.+IMMUNOCOMP.(5%)

IO PROGRESSIVE: PEDS.+IMMUNOCOMP.(5%)

REACTIVATION/ADULTS(5-10%)

REACTIVATION/ADULTS(5-10%)

INFECTION(90+%)

INFECTION(90+%)

Time (mos-yrs)

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Pulmonary Tuberculosis(slide 1)

Pulmonary Tuberculosis(slide 1)

• Cough (+/-RBC), Wt. Loss, Night sweats• 109-1011 CFU• Diagnosis: Sputum Smear/Culture

(<50% paucibacillary)• Pathology: Caseating Granulomas,

Necrosis, Cavitation (?Host or Microbe)• Death:

– Cachexia– Respiratory Failure– Dissemination (miliary, meningitis)– Massive Hemoptysis

• Cough (+/-RBC), Wt. Loss, Night sweats• 109-1011 CFU• Diagnosis: Sputum Smear/Culture

(<50% paucibacillary)• Pathology: Caseating Granulomas,

Necrosis, Cavitation (?Host or Microbe)• Death:

– Cachexia– Respiratory Failure– Dissemination (miliary, meningitis)– Massive Hemoptysis

http://library.med.utah.edu/WebPath

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Immunology of M. tuberculosis infection and disease (slide 2)

Immunology of M. tuberculosis infection and disease (slide 2)

-TCRCD 4T cell

class II MHCclass I MHC

-TCR

CD 8T cell

DN TCRCD1 restricted T cells

M

-TCR

T cell

Phos. Ag

CD25+ CD4 T cell

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REACTIVATIONREACTIVATION

INFECTIONINFECTION

Innate Adaptive Failure (Immunopathogenesis?)

• TLR’s• Chemokines• Cytokines• Antigens• T cell subsets• Effector mech.• Immune evasion

• TLR’s• Chemokines• Cytokines• Antigens• T cell subsets• Effector mech.• Immune evasion

“Known knowns, known unknowns, unknown unknowns” and dogma for immunology of human TB

(slide 3, “adapted from Donald Rumsfeld ‘03”)

“Known knowns, known unknowns, unknown unknowns” and dogma for immunology of human TB

(slide 3, “adapted from Donald Rumsfeld ‘03”)

• Known:– Adaptive immunity– CD4+ T cell– TNF-alpha– IFN-gamma– IL-12

• Unknown:– Genetics: which ones/stage

(IFNgamma/IL12 pathway, NRAMP1, TNFalphaR, etc.)

– TLRs: which ones/when– Chemokines: same (MCP1)?– What does IFN-gamma do?– Immunology of the lung: why

so slow?– Antigens matter: which ones,

when, where?

• Known:– Adaptive immunity– CD4+ T cell– TNF-alpha– IFN-gamma– IL-12

• Unknown:– Genetics: which ones/stage

(IFNgamma/IL12 pathway, NRAMP1, TNFalphaR, etc.)

– TLRs: which ones/when– Chemokines: same (MCP1)?– What does IFN-gamma do?– Immunology of the lung: why

so slow?– Antigens matter: which ones,

when, where?

• Dogma:

– “Immuno-pathogenesis”

(HIV: cavitation related to CD4, but mortality still high)

– CD8’s critical, cause of BCG failure

– It is all about cytokines (cytokine interventions have failed)

– Now it’s Tregs, Th17………

• Unknown unknowns:– TLRs in last century– Why all T cell vaccines have

failed so far (TB, HIV)?

• Dogma:

– “Immuno-pathogenesis”

(HIV: cavitation related to CD4, but mortality still high)

– CD8’s critical, cause of BCG failure

– It is all about cytokines (cytokine interventions have failed)

– Now it’s Tregs, Th17………

• Unknown unknowns:– TLRs in last century– Why all T cell vaccines have

failed so far (TB, HIV)?

T

M

TNF-, IL-12

IFN-

Cytokines and M. tuberculosisCytokines and M. tuberculosis

• IFN-– IFN-R deficient humans

– IFN- KO mice

• TNF-– TNF- and TNF-R KO mice – anti-TNF- antibodies in humans

• IL-12– IL-12R deficient humans – IL-12 KO mice

• IL-10/TGF-– Inhibit during active disease

• IFN-– IFN-R deficient humans

– IFN- KO mice

• TNF-– TNF- and TNF-R KO mice – anti-TNF- antibodies in humans

• IL-12– IL-12R deficient humans – IL-12 KO mice

• IL-10/TGF-– Inhibit during active disease

T M

TNF-, IL-12

IFN-, IL-10

Immune Evasion by M. tuberculosisImmune Evasion by M. tuberculosis

• Innate:– Blocks Phagosomal Maturation

• Limited fusion with lysosomes• Exclusion Na+ Dep. Proton ATP-ase• Retains Rab5 delays Rab7 acquisition • ? Sticking TACO-tryptophane aspartate-containing coat protein (murine)• Inhibition of Ca2+ rise prevents calmodulin/CaMKII recruitment of cathepsinD• Roles for LAM, PIM

– Inactivates Bactericidal Mechanisms• oxygen radicals• nitric oxide• autophagy

• Adaptive:– Inhibition of IFN-gamma regulated genes– Inhibition of MHC II Antigen Processing

(lipoproteins/TLR-2)– Direct modulation of CD4+ T cell function– Inhibitory Cytokines (IL-10, TGF-beta)– T cell Apoptosis

• Innate:– Blocks Phagosomal Maturation

• Limited fusion with lysosomes• Exclusion Na+ Dep. Proton ATP-ase• Retains Rab5 delays Rab7 acquisition • ? Sticking TACO-tryptophane aspartate-containing coat protein (murine)• Inhibition of Ca2+ rise prevents calmodulin/CaMKII recruitment of cathepsinD• Roles for LAM, PIM

– Inactivates Bactericidal Mechanisms• oxygen radicals• nitric oxide• autophagy

• Adaptive:– Inhibition of IFN-gamma regulated genes– Inhibition of MHC II Antigen Processing

(lipoproteins/TLR-2)– Direct modulation of CD4+ T cell function– Inhibitory Cytokines (IL-10, TGF-beta)– T cell Apoptosis

NIAID-DMID: -AI70022

Models for what aspect of TB?Models for what aspect of TB?

• Pathology-granuloma, lung pathology, cavity, caseation (rabbit)

• Immunology-innate vs. adaptive T cell immunity (mouse, primate,?bovine)

• Genetics- risk for infection, progression, reactivation vs. relapse (?mouse, bovine)

• Drug Treatment-latent vs. active infection (efficacy, PK, ARV interactions) (primate)

• Vaccine- infection, dissemination vs. re-activation (mouse, guinea pig, primate)

• Co-pathogenesis-HIV or helminth co-infection (primate)

• Pathology-granuloma, lung pathology, cavity, caseation (rabbit)

• Immunology-innate vs. adaptive T cell immunity (mouse, primate,?bovine)

• Genetics- risk for infection, progression, reactivation vs. relapse (?mouse, bovine)

• Drug Treatment-latent vs. active infection (efficacy, PK, ARV interactions) (primate)

• Vaccine- infection, dissemination vs. re-activation (mouse, guinea pig, primate)

• Co-pathogenesis-HIV or helminth co-infection (primate)

Protective Adaptive Immunity to M. tuberculosis: Macrophages and T cells

Protective Adaptive Immunity to M. tuberculosis: Macrophages and T cells

• IL-12, TNF-alpha, IFN-gamma

• IL-2 for T cell expansion

• Cytotoxic Effector T Cells (CTL)• Growth inhibition of M. tuberculosis

• IL-12, TNF-alpha, IFN-gamma

• IL-2 for T cell expansion

• Cytotoxic Effector T Cells (CTL)• Growth inhibition of M. tuberculosis

T cell

M

CTL

cytokines

IL-12, IFN-, TNF-

(FasL/CD95L, granzymes, perforin, granulysin)

Growth inhibition

IL-2