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
IFNR
STAT1
IL-12
1 2
IRF8
ISG15
NEMO
AFB Salm.
TNF NRAMP1
M CD14
TNFR
TLR LPS
IL-2
One Major Pathway
IL-2R
IFN
T / NK
IL-12R IL 12R
18
?
IL 15 IL-
GATA2
IFNR
STAT1
IL-12
1 2
IRF8
ISG15
NEMO
AFB S l Salm.
TNF TNF
NRAMP1
M CD14
TNFR 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
IFNR
STAT1
IL-12
1 2
IRF8
ISG15
NEMO
AFB Salm.
TNF NRAMP1
M CD14
TNFR
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
IFNR
STAT1
IL-12
1 2
IRF8
ISG15
NEMO
AFB Salm.
TNF NRAMP1
M CD14
TNFR
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
IFNR
STAT1
IL-12
1 2
IRF8
ISG15
NEMO
AFB Salm.
TNF NRAMP1
M CD14
TNFR
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