anti ifn-gamma autoantibody associated with adult-onset immunodeficiency

Autoantibody to Interferon-gamma

Associated with Adult-Onset Immunodeficiency

Suda Sibunruang, M.D.

Outline • Reported cases

• Interferon and interleukin-12 pathways

• Natural anti–INF- antibodies

• Landmark study & present data

• Associated reactive dermatoses

• Autoantibodies to cytokines

• Mendelian susceptibility to mycobacterial infection

• Prognosis

• Treatment

ทมแพทย รพ.ศรนครนทร ม.ขอนแกน คนพบ“โรคภมคมกนบกพรองทไมใชเอดส”

เปนครงแรกของโลก (พ.ศ.2543)

Access from www.kku.ac.th and www.rcpt.org January 2, 2015

AIDS-like illness which occurs in otherwise immunocompetent adults

http://www.kku.ac.th/

http://www.rcpt.org/

Lamb RC. et al. International Journal of Dermatology 2014;53:1197–204

Non-tuberculous mycobacteria (NTM)

Lamb RC. et al. International Journal of Dermatology 2014;53:1197–204 Picture from www.drugline.org, Access January 8,2015

• NTM can be isolated from soil, dust, water, vegetation, animals, and hospital environments • Tap water is the main reservoir for most human NTM

http://www.drugline.org/

Chetchotisakd P. et al. Clin Infect Dis 2000;30:29–34

Reported 16 cases of rapidly growing Mycobacterium (RGM) from 1994 - 1998 • All had chronic bilateral cervical lymphadenopathy • 12/16 had involvement of other organs (sinuses, 6; lungs, 4; liver, 4; spleen, 3; skin, 3; bone and joint, 2; and tonsils, 2)


• 11/16 had 14 episodes of reactive skin manifestations (Sweet’s syndrome, 9; generalized pustulosis and erythema nodosum, 2 each; and pustular psoriasis, 1) • 8/16 had 11 episodes of other opportunistic

pathogens (salmonellosis, 4; penicilliosis, 3; pulmonary tuberculosis, 2; and melioidosis and cryptococcosis, 1 each)


From 1994-2006, there were 129 cases • All patients but 1 were adults • 99 cases due to RGM and 34 due to SGM


21/129 (16.3%) patients had positive results of blood cultures

Infected with other intracellular pathogens


The majority of patients had Sweet syndrome as their first presentation along with cervical lymphadenopathy


Sweet syndrome NTM involved skin


Anti–IFN- IgG autoantibodies were also present in 5 anonymous serum samples obtained

from the patients tested

Hoflich C. et al. Blood. 2004;103:673-5

A 25-year-old Thai woman, Anti – HIV – negative • Necrotizing lymphadenitis, tonsillitis, bilateral pneumonia, splenic and intracerebral abscesses, and osteomyelitis from Burkholderia cocovenenans (16S rDNA sequence)

• Fatal septic shock from Mycobacterium chelonae

Concanavalin A stimulation

• Whole blood stimulation revealed no detectable IFN- production, whereas IL-4 production was unaffected

• Intracellular IFN- staining of whole blood cells following stimulation was positive

• Stimulation of PBMCs showed normal levels of IFN- secretion

• Inhibitory IFN- activity in the patient’s plasma



Add recombinant IFN- to the patient’s plasma and measuring IFN- concentration by ELISA


PBMCs from a healthy volunteer were incubated with IFN- in the presence of either patient’s plasma or control plasma

Absence of autologous plasma, the patient’s PBMCs responded normally to exogenous and endogenous IFN-


High-affinity IFN-–binding activity is an anti–IFN- IgG4 autoantibody

However, the pathogenesis of autoantibody formation to IFN- in this patient remains unclear

Doffinger R. et al. Clin Infect Dis 2004;38:e10-4

Autoantibodies to Interferon- in a Patient with Selective Susceptibility to Mycobacterial

Infection and Organ-Specific Autoimmunity

A 47-year-old, previously fit, Filipino man • Disseminated Mycobacterium tuberculosis • Disseminated Mycobacterium chelonae



Infection and Organ-Specific Autoimmunity Anti–IFN- activity

Impaired IFN- and IL-12 secretion

PBMC + 5% autologous serum



Infection and Organ-Specific Autoimmunity

Mendelian defects in IL-12–dependent INF- pathway were excluded by sequencing the IFNGR1, IFNGR2,

STAT1, IL12B, and IL-12RB1 genes


A year after the patient commenced IFN- therapy

• recurrent candidiasis

The patient died of overwhelming mycobacterial infection

Similar to autoimmune polyendocrinopathy candidiasis- ectodermal dystrophy

From 2004-2005 • 11 cases from 4 reports

• 8/11 were Asians

5 were Filipino

1 was Taiwanese

1 was Vietnamese

1 was Thai

Hoflich C. et al. Blood. 2004;103:673-5 Doffinger R. et al. Clin Infect Dis 2004;38:e10-4

Kampmann B. et al. J Clin Invest 2005;115:2480-8 Patel SY. et al. J Immunol 2005;175:4769-76

Interferon- and interleukin-12 pathways

Dorman SE and Holland SM Cytokine & Growth Factor Reviews 2000;11;321-33

p35

p40


• Production of cytokines and chemokines • Enhancement TNF- production • Upregulation of MHC class II expression • Enhancement antigen processing • Production of reactive oxygen and nitrogen intermediates (in mice)

Main regulatory pathway of cell-mediated immunity


IFNGR1 gene is located on chromosome 6 IFNGR2 gene is located on chromosome 21


IFNR1/IFN complex

IFN-responsive genes

• Antiviral activity • Apoptosis, • Antigen processing • MHC expression • TH1 development • Activates macrophages

Casanova JL. Swiss Med Wkly 2001;131:445-54

Doffinger R. et al. Curr Opin Rheumatol 2005;17:440—6

Bacterial ligands like mycobacterial lipoarabinomannan

Natural anti–INF- antibodies

Have been reported in patients with

• Tuberculosis

• Viral diseases

• Healthy subjects

• HIV-infected individuals

• Experimental African trypanosomiasis


But the potential pathogenic impact of these antibodies has not been established

Madariaga L. et al. Int J Tuberc Lung Dis 1998;2:62-8

Anti–IFN- antibodies

Autoantibody titres correlated with serum interferon- concentrations

Caruso A. et al. J Immunol 1990;144:685-90

180 Healthy individuals

Caruso A. et al. J Immunol 1990;144:685-90

Titer of anti-IFN- antibodies during a viral infection

Infectious mononucleosis

Varicella

Measles

Healthy persons

Natural anti–INF- antibodies in healthy patients were detected in low titers and

been biologically inactive without antagonist activity against IFN- signaling

Lee WI. et al. Immunobiology 2013;218:762–71

Browne SK et al. N Engl J Med 2012;367:725-34

Methods

Enrolled 203 persons from Thailand and Taiwan

• Group 1: 52 patients with disseminated, rapidly or slowly growing, nontuberculous mycobacterial (NTM) infection

• Group 2: 45 patients with another opportunistic infection, with or without NTM infection

• Group 3: 9 patients with disseminated tuberculosis

• Group 4: 49 patients with pulmonary tuberculosis

• Group 5: 48 healthy controls


Browne SK et al. N Engl J Med 2012;367:725-34 (supplementary appendix)

Group 1 - 4


Normal range was defined “ 99th percentile for the patients with pulmonary TB and

the healthy controls combined ”


Anti–Interferon- autoantibody concentrations according to study group

Group 1 & 2

99 percentile

These anti–interferon- autoantibodies did not block STAT1 phosphorylation


Anti–IFN- autoantibody levels

Although antibody levels may decrease with disease quiescence, they can

persist for years


Forty other anticytokine autoantibodies were assayed


STAT1 phosphorylation

However, permitting interferon-α–induced STAT1 phosphorylation


• Absence of familial clustering • Normal expression of interferon- receptor 1 • Lymphocytes count (including CD4+ T cells) were normal

Remarks • Trigger for production of these

autoantibodies remains elusive

• Nearly all patients identified have been Asian-born Asians, implicates host genetic factors, environmental exposure, or both


Chi CY. et al. Blood 2013;121:1357-66

HLA-DRB1*16:02 (odds ratio 8.68; 95%CI, 3.47-21.90) HLA-DQB1*05:02 (odds ratio 7.16; 95%CI, 3.02-17.05) were found in 82% (14 of 17) of our patients

Genetic risk factors ?

Genetic risk Factors ? Even the largest cohort of patients

• No familial clustering

• Few reported in Asians born outside of Asia

Browne SK. et al. Annu Rev Immunol 2014;32:635–57

Suggesting 1. Genetics are likely complex 2. Environmental factors, possibly early in life, may contribute to

Wongkulab P. et al. PloS One 2013;8:e76371


Mean 2.460 ± 1.309 O.D. among cases Mean 0.058 ± 0.004 O.D. among HIV Mean 0.059 ± 0.005 O.D. among controls

n 20 20 20

Tang B. et al. CLINICAL AND VACCINE IMMUNOLOGY 2010;17:1132–8

Subgroup analysis: • level of autoantibody in patients with active infections was relatively higher than those without (mean 3.279 ± 0.662 Vs 0.939 ± 0.630 O.D.) • level of autoantibody may have a role in monitoring disease activity or recurrence of the disease


Wipasa J. et al. PloS One 2014;10:e110276

- No differences in %monocytes, CD 68 and HLA-DR - Normal inducible nitric oxide synthase (iNOS) production (not shown) - Higher CD119, suggesting the presence of activated monocytes in the circulation

Wipasa J. et al. PloS One 2014;10:e110276

This adult-onset immunodeficiency may be associated with one or more of the abnormal immune responses

Mitogen stimulation


Normal genetic sequencing or/and candidate protein expressions of IFN-R1, IFN-R2, IL-12p40, IL-12R-1,

STAT-1, NEMO, IKBA, CYBB and IRF8

Suggest including anti-IFN- autoantibodies

in the differential diagnosis of

• HIV-negative adult patients with unknown cell-mediated immunodeficiency

• Severe, persistent or recurrent infections caused by NTM

or Salmonella

• Especially in Asian patients

• Reactive skin lesions or autoimmune endocrinopathy

Kampitak T. et al. Infection 2011;39:65–71

Chan J et al. Dermatology 2013;226:157–66


1. Progressive painful erythematous papules over 2 weeks


2. Multiple painful non-ulcerated infiltrated plaques


3. Progressively enlarging erythematous scaly non-painful nodules


1. Suppurative inflammation sparing the epidermis -> Sweet’s syndrome

Chan J et al. Dermatology 2013;226:157–66 2. Lobular panniculitis

Chan J et al. Dermatology 2013;226:157–66 3. Multiple epitheloid granulomas -> skin infection by NTM

Different forms of dermatoses

Broadly classified into

• Reactive dermatoses

- Sweet’s syndrome

- Erythema nodosum

- Lobular panniculitis

- Generalized pustular eruptions (AGEP,

pustular psoriasis and subcorneal pustulosis)

• Direct invasion of the skin in disseminated infection


-> most common

Cohen PR. Orphanet Journal of Rare Diseases 2007;2:34

Sweet's syndrome can present in several clinical settings: - Classical (or idiopathic) - Malignancy associated - Drug-induced


Diagnostic criteria for classical Sweet's syndrome

Major

Minor

Both major criteria, and 2/4 of minor criteria


Papillary dermal edema, swollen endothelial cells

Diffuse infiltrate of neutrophils

Chiewchanvit S. et al. J Med Assoc Thai 2013;96:1609-16

Acitretin, a second-generation retinoid, have been reported in the treatment of pustular diseases

including pustular psoriasis, subcorneal pustular dermatosis, eosinophilic pustular

folliculitis, and AGEP

Chiewchanvit S. et al. J Med Assoc Thai 2013;96:1609-16

Autoantibodies to cytokines

Browne SK. Annu. Rev. Immunol. 2014;32:635–57

Autoantibodies to cytokines

• Occur in many different conditions

• May also develop against exogenously cytokines

• Have been identified in health and disease, with their relationship ranging from none to directly causal

Browne SK and Holland SM. Lancet Infect Dis 2010;10:875-85

Mendelian susceptibility to mycobacterial infection (MSMD)

Mendelian susceptibility to mycobacterial infection

• Selective susceptibility to weakly pathogenic mycobacteria, such as BCG vaccine and environmental NTM causing idiopathic, disseminated infection, has long been suspected to be a Mendelian disorder


Muhsen SA and Casanova JL. J Allergy Clin Immunol 2008;122:1043-51

Geographical origin of kindreds with genetic defects of MSMD

Not confined to a particular ethnic group or geographic region

Vosse E. and Ottenhoff T. Microbes and Infection 2006;8:1167-73

Access January 8, 2015

Casanova JL. Swiss Med Wkly 2001;131:445-54 Muhsen SA and Casanova JL. J Allergy Clin Immunol 2008;122:1043-51

Six genes have been found to be mutated

IFNGR1 & IFNGR2

STAT 1

IL12 p40 IL12RB1

NEMO

Nine different inheritable disorders

• Two forms of complete recessive IFN R1 deficiency

• Complete IFN R2 deficiency

• Partial recessive IFN R1 deficiency


• Partial dominant IFN R1 deficiency

• Partial STAT-1 deficiency

• Complete IL-12 p40 deficiency

• Complete IL-12R1 deficiency






• Early childhood ( < 3 yr) • Overwhelming infections • Lesions are multibacillary • Impaired granuloma formation









• Various ages • Curable infections • Lesions are paucibacillary • Mature granulomas

Vosse E. et al. Lancet Infect Dis 2004;4:739–49

Till…2013 25 reported cases from PubMed search

• Majority of cases were Asian (8 Chinese, 6 Filipino, 4 Thai, 4 Taiwanese, 2 Japanese, and 1 Vietnamese)

• Organs involved were the lymph nodes (22), lungs (19), bones (12), soft tissue (9), bone marrow (7), and skin (7)


Till…2013 • Tissue cultures and pathology findings

rather than blood cultures provided evidence of NTM

• Both slow- and rapidly growing NTM were causative pathogens, with Mycobacterium avium complex (14) and M. chelonae (7)

• 6 patients were infected with multiple species of mycobacteria, including both NTM and M. tuberculosis


Till…2013 • Co-infections with P. marneffei and

Salmonella spp. simultaneously developed in 11 and 7 patients

• Experience both dermatomal and disseminated varicella zoster reactivation at higher frequency

Lee WI. et al. Immunobiology 2013;218:762–71 Browne SK. et al. Annu Rev Immunol 2014;32:635–57

Till…2013 • Laboratory features often indicative of

chronic inflammation or infection, including anemia, leukocytosis, elevated ESR, CRP, and/or β2-microglobulin and polyclonal hypergammaglobulinemia


Till…2013 • grossly normal immunologic

parameters, including CD4+ T lymphocytes, monocyte numbers, and IFNγR1 expression


Browne SK and Holland SM. Current Opinion in Allergy and Clinical Immunology 2010;10:534–41

Prognosis • 32% mortality by a median of

25 months after diagnosis


Treatment

Treatment

• Treating the disease consequences

• Targeting the autoantibody


Treatments • Majority fail to show a sustained

response to IFN- treatment

• IVIG for neutralizing and plasmapheresis to remove antibody, are not consistently effective


Browne SK et al. Blood 2012;119:3933-9

Rituximab was used in 4 patients with high-titer anti–IFN- autoantibodies who had progressive refractory NTM disease despite aggressive anti-infective treatment • Treat according to a lymphoma regimen, additional doses were given for persistence or relapse • Aim of depleting B cells • Other possible mechanisms; modulation cell surface receptors, modulation B-cell, elimination plasmablasts


Rituximab was given at 375mg/m² weekly x 4 doses, then at wider intervals

8 - 12 doses over the first year


Within 2-6 months after treatment, all patients had marked clinical, radiologic, and laboratory improvement

Conclusion • Not all cases of anti–IFN- autoantibody-

mediated disseminated mycobacterial disease require rituximab

• Recommend for those with persistent, progressive, severe anti–IFN- autoantibody–associated infection


Czaja C. et al. Clin Infect Dis 2014;58:e115–8

Future well controlled studies are needed to

evaluate the safety and efficacy of this approach

Take home messages (1) Suggest including anti-IFN- autoantibodies

in the differential diagnosis of

• HIV-negative patients

• Severe, persistent or recurrent infections caused by NTM and other opportunistic infections

• Reactive skin dermatoses

• Especially in Asian patients

Take home messages (2) • Trigger for these autoantibodies

remains unknown

• Patients with genetic defects tend to present early in life, and often show familial clustering

Thank you for your attention

anti ifn-gamma autoantibody associated with adult-onset immunodeficiency

Health & Medicine

skin chetchotisakd

blood stimulation

sgm chetchotisakd

human ntm chetchotisakd

ifn concentration

recombinant ifn

blood cells

patients plasma hoflich