Late Onset L O Immunodeficiencies Steven M M. Holland Holland, MD Laboratory of Clinical Infectious Diseases gy and Infectious National Institute of Allergy Diseases [email protected]

Adult Onset Immunodeficiencies? (Infections normal healthy people are not supposed to have)

HIV Diabetes Age‐related senescence Lymphoma Leukemia Thymoma Steroids D t Doctors

Mycobacteria M tuberculosis M. t b l i

K h 1882 Koch,

M. kansasii Bacille Calmette-Guerin M leprae M. M. avium complex

Relative Virulence

M. abscessus M. fortuitum

NTM

M. gordonae M. smegmatis

Clinical Spectrum of NTM Infections Skin

Disseminated

Exposure Inoculation

Severe, Young Immune defects

Pulmonary Chronic, Ch i Old Older Bronchiectasis Cysticc fibrosis Cyst b os s (CF) (C ) Ciliary dyskinesia (PCD)

IL-2

Mycobacterial Control

IL-2R

IFN

T / NK

IL 12R IL-12R

  18

?

IL- 15

GATA2

IFNR

STAT1

IL-12

1 2

IRF8

ISG15

NEMO

AFB Salm.

TNF NRAMP1

M CD14

TNFR

TLR LPS

IL-2

One Major Pathway

IL-2R

IFN

T / NK

IL-12R IL 12R

  18

?

IL 15 IL-

GATA2

IFNR

STAT1

IL-12

1 2

IRF8

ISG15

NEMO

AFB S l Salm.

TNF TNF

NRAMP1

M CD14

TNFR LPS

TLR

Pathogens in human IFN/IL-12 defects: Intracellular Pathogens Nontuberculous mycobacteria y ((NTM)) Bacille Calmette Guerin (BCG) M. tuberculosis (MTB) Salmonella Burkholderia Listeria Histoplasma C idi id Coccidioides VZV, CMV, HSV, HHV-8 RSV

IL-2

One Major Pathway Most IFN in Childhood

IL-2R T / NK

IL 12R IL-12R

  18

?

IL- 15

GATA2

IFNR

STAT1

IL-12

1 2

IRF8

ISG15

NEMO

AFB Salm.

TNF NRAMP1

M CD14

TNFR

TLR LPS

60 yo Vietnamese woman  Moved to USA 1970s 1 year recurring disseminated  M. avium complex p Numerous fistulae

What is Causing this Late Onset  Immunodeficiency? d f The infections suggest IFN/IL 12 pathway The infections suggest IFN/IL‐12 pathway. The age is late for a typical primary  immunodeficiency. Genetic testing did not find a cause Genetic testing did not find a cause.

IL-2

IL-2R

IFN

T / NK

IL 12R IL-12R

Where is the Lesion?

  18

?

IL- 15

GATA2

IFNR

STAT1

IL-12

1 2

IRF8

ISG15

NEMO

AFB Salm.

TNF NRAMP1

M CD14

TNFR

TLR LPS

59 Adult Thai Cases of NTM with Coinfections

Chetchokisakd P, Clinical Infectious Diseases, 2000

Disseminated P i illi marneffei Penicillium ff i M. fortuitum

Salmonella lymphadenitis

M. abscessus

Cryptococcosis

Neutrophilic pustulosis

Sweet’s Syndrome

41 autoantibodies tested by LIPS (L if (Luciferase Immunoprecipitation) I i i i ) 7 6 5 4 3 2

Only IFN autoantibodies count Only IFN autoantibodies count 7

Anti-IFN Anti IFN

6 5 4 3 2

41 autoantibodies tested by LIPS (Luciferase)

Inhibition is in the plasma, cells OK Inhibition is in the plasma, cells OK Calf Serum

Patient Serum

TNF production: LPS alone vs LPS+IFN

IL-2

IL-2R

IFN

T / NK

IL 12R IL-12R

Anti-IFN Autoantibody

  18

?

IL- 15

GATA2

IFNR

STAT1

IL-12

1 2

IRF8

ISG15

NEMO

AFB Salm.

TNF NRAMP1

M CD14

TNFR

TLR LPS

NEJM 2012;367:725

Some Patients Do Not Have Anti‐IFN Autoantibodies NTM

OI

Pulmonary and CNS Cryptococcosis Pulmonary TB

LIPS 7

Anti GM CSF Anti-GM-CSF

6 5 4 3 2

Rosen et al, J Immunol March 18, 2013

The Journal of Immunology, 2013, 190: 3959–3966.

CNS Nocardia

43 year old soldier Healthy, active duty Acute seizure Brain biopsy: pus Culture: Nocardia Chest CT: Rare ground glass opacities Pulmonary function: normal

Anti-GM-CSF in Plasma of CNS Nocardia Patients

Patient 1 Patient 2 Controls (n=10)

10000

5000

Fα TN

2 -2 IL

7A IL

2p -1

-1

70

-6

γ N IF

α N IF

IL IL

M

-C

SF

0

G

Fluorescence Intensity

15000

Anticytokine Autoantibodies Adult onset immunodeficiency y 90% of Thai patients with severe infection had neutralizing g anti-IFN autoantibodies In US, Anti-IFN mostly in East Asians, mostly women Anti-GM-CSF autoantibodies in pulmonary and g cryptococcosis yp and Nocardia meningeal Treatment: antibiotics/antifungals, Rituximab More to Come

Acknowledgements Autoantibodies Sarah K. K Browne Smita Patel Lindsey Rosen Emilyy Rosen Rifat Zaman Allen Mo Nok Kamerwon Ploenchan Chetchokisakd Lisa Barnhart Reggie Claypool M j H Margje Haverkamp k Hannelore Bax Li Ding

GATA2 Amyy P. Hsu Elizabeth Sampaio Smita Patel Josh Milner Liana Falcone Jennifer Leiding Ken Olivier Gulbu Uzel Alexandra Freeman Christa Zerbe Don Vinh Maria L. L Turner Emery Bresnick Kirby Johnson Jennifer Cuellar-Rodriguez Dennis Hickstein

STAT1 Amy P. Hsu Elizabeth Sampaio Ken Olivier Josh Milner Gulbu Uzel Joseph Pecacek Mary y Hanks Troy Torgerson Eleonora Gambinieri Douglas Kuhns