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

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-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)?

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Panel III: Immune RelevancyPanel III: Immune Relevancy

Sacred “cows”, questions and other musings

Sacred “cows”, questions and other musings

Questions to consider…..Questions to consider…..• Can host responses/markers tell us when infection

progresses to disease?– Or is it detecting something from MTB that tells us CFUs are

increasing?

• Is Th1 vs. Th2 paradigm (still) useful?– Ineffectual/failed Th1 rather than Th2?

• Balance of cytokines or do antigens matter?– For vaccines likely? For progression maybe not? For

relapse/reinfection don’t know?

• Evidence that host responses are responsible for pathology?– Aren’t granulomas in the right places good? Does it depend on

the stage of infection? Can we intervene to prove it?

• What’s up with the lungs?– Why the sluggish response? What is unique about the lungs as

immune environment/sanctuary for MTB?

• Can host responses/markers tell us when infection progresses to disease?– Or is it detecting something from MTB that tells us CFUs are

increasing?

• Is Th1 vs. Th2 paradigm (still) useful?– Ineffectual/failed Th1 rather than Th2?

• Balance of cytokines or do antigens matter?– For vaccines likely? For progression maybe not? For

relapse/reinfection don’t know?

• Evidence that host responses are responsible for pathology?– Aren’t granulomas in the right places good? Does it depend on

the stage of infection? Can we intervene to prove it?

• What’s up with the lungs?– Why the sluggish response? What is unique about the lungs as

immune environment/sanctuary for MTB?

How can natural/experimental infection in animals help with these questions?

How can natural/experimental infection in animals help with these questions?

• Natural history of infection and progression to disease (many)– Transition between stages/markers of transition

• Pathology-granuloma, caseation, cavitation (rabbit, guinea pig)– MTB mutants/host genetic variants that differ in induction of

pathology with similar CFU

• Role of innate vs. adaptive immunity (mouse, primate, bovine)– Models difficult to infect, innate KO’s

• Genetics of different stages (mouse, bovine, fish, ?others)– Infection, progression, reactivation vs. relapse

• Drug Treatment (mouse, rabbit, primate, fish)– Latent vs. active infection (penetration/efficacy, PK, ARV)

• Vaccine (mouse, guinea pig, primate, bovine)– Infection, dissemination vs. re-activation

• Co-pathogenesis-HIV or helminth co-infection (primate)– Maybe asking too much…….

• Natural history of infection and progression to disease (many)– Transition between stages/markers of transition

• Pathology-granuloma, caseation, cavitation (rabbit, guinea pig)– MTB mutants/host genetic variants that differ in induction of

pathology with similar CFU

• Role of innate vs. adaptive immunity (mouse, primate, bovine)– Models difficult to infect, innate KO’s

• Genetics of different stages (mouse, bovine, fish, ?others)– Infection, progression, reactivation vs. relapse

• Drug Treatment (mouse, rabbit, primate, fish)– Latent vs. active infection (penetration/efficacy, PK, ARV)

• Vaccine (mouse, guinea pig, primate, bovine)– Infection, dissemination vs. re-activation

• Co-pathogenesis-HIV or helminth co-infection (primate)– Maybe asking too much…….