Mendelian susceptibility to mycobacterial diseases

Mendelian susceptibility
to mycobacterial diseases : MSMD
12th March 2021
Nattasasi Suchamalawong, MD.
Pediatric Allergy and Immunology Unit
King Chulalongkorn Memorial Hospital

• Case study
• Definition
• Pathogenesis:
Interferon gamma – IL 12 signaling pathways
• Genetic etiologies of MSMD
• Clinical features
• Diagnosis
• Differential diagnosis
• Investigation
• Treatment
• Prognosis
Outline

A 20-years-old, Thai man previous healthy , unknown underlying disease
CC: chronic abdominal pain with abdominal distension with weight loss for 6 months
PI: 1 day PTA abdominal distension with diarrhea
PE: vital sign: BT 38.0 c, PR 100/min, RR 24/min, BP 124/82 mmHg
HEENT: markedly pale conjunctivae ,no oral ulcer seen tonsil size 2+
Heart: normal S1S2, no murmur Lungs: clear , equally breath sound
Abdomen: moderate distension, moderate tender at Rt sides abdomen
and epigastrium, liver and spleen can’t be palpated
FH: No family history of PID or unusual death
Investigation >> film acute abdomen : suspected gut obstruction.
Consult Sx : suspected gut obstruction plan set OR for explore laparotomy
Case 1

Case 1: physical examination
PE: BW 71 kg (78 →71 kg in 3 months), HT 160 cm
• No dysmorphic feature , prognathism
• Vital sign: BT 38.0 c, PR 100/min, RR 24/min, BP 124/82 mmHg
• HEENT: markedly pale conjunctivae ,seen tonsil size 2+
• Heart: normal S1S2, no murmur
• Lungs: clear , equally breath sound ,
• Abdomen: moderate distension, moderate tender at Rt sides abdomen
and epigastrium, liver and spleen can’t be palpated
• Skin : multiple discrete hyperpigmented papule symmetrical at both leg
• Lymph node : no superficial lymphadenopathy

Case1: Lab investigation
CT Whole abdomen 17/7/63
- Mildly thickened wall of small and large bowel complex rim-enhancing
fluid collection in pelvic cavity DDx is tuberculosis.
- Multiple enlarged necrotic nodes involving at paraaortic, aortocaval and
mesenteric region
- Multiple groups of centrilobular and ground-glass nodules, some with t
ree-in bud, at superior segment of
LLL, probably aspiration or infection/inflammation process.
- Several small nodules in RLL with moderate right pleural effusion.
CXR 17/7/63:
RLL infiltration , no widening
mediastinum

Chemistry 17/3/63
BUN 11 mg/dL
Creatinine 0.6 mg/dL
Na 131 mmol/L
K 3.1 mmol/L
Cl 106 mmol/L
HCO3 22 mmol/L
Calcium 7.8/8.8 mg/dL
Magnesium 0.8 mg/dL
Phosphate 2.4 mg/dL
LFT 17/3/63
AST 14 U/L
ALT 6 U/L
ALP 113 U/L
TB 2.6 mg/dL
DB 1.23 mg/dL
Albumin 2.7 g/dL
Globulin 3.5 g/dL
Culture
Tracheal suction G/S No organism
Tracheal suction C/S No growth
Tracheal suction AFB Positive 1+
Sputum PCR for MTBC Detected
C/S for TB Mycobacterium
tuberculosis
LPA MTBC+,
sense I, R
AFB negative
AFB negative
Sputum PCR for MTBC Detected
Blood C/S for TB Negative
CBC 16/3/63
Hb 6.6 g/dL
Hct 22.9 %
MCV 88.8 Fl
RDW 12.8 %
WBC 11,870 /ul
Neutrophil 86 %
Lymphocyte 13 %
Monocyte 0.2 %
Eosinophil 0 %
Basophil 0.8 %
Platelets 454,000 /ul
ANC 10,208
ALC 1,543
Ascites
Tissue (necrotic node)
,Pus wound , Stool
H/C (20/7/63): no growth
Anti-HIV : negative

CBC 16/7/63 17/7/63 18/7/63 19/7/63 20/7/63
Hb 6.6 8 9.2 9.3 8.2 g/dL
Hct 22.2 25.4 28.4 29.2 25.2 %
MCV 88.8 86.7 85.8 85.1 85.7 Fl
RDW 21.8 19.9 17.5 17.34 17.1 %
WBC 11,870 12,820 10,720 8,630 6,520 /ul
Neutrophil 86 88.2 86.9 88 81.2 %
Lymphocyte 13 5.2 4.3 3.6 6.3 %
Monocyte 1 5.2 7.3 5.9 9.5 %
Eosinophil 0 0.5 0.9 1.6 2.1 %
Basophil 0 0.9 0.6 0.9 0.9 %
Platelets 454,000 447,000 335,000 323,000 261,000 /ul
ANC 10,208 11,300 9,320 7,590 6,300
ALC 1,543 670 460 310 410
Strat IRZE

Case 1: Problem list
1. Disseminated TB
(Sputum AFB positive , small bowel caseous granuloma ,
LN AFB negative (necrotizing granulomatous lymphadenitis))
2. Lymphopenia with anemia
3. hyperpigmented papule symmetrical at both leg
4. History of chronic rhinitis , seafood allergy
Management :
- Ceftriaxone 2 g IV OD (17/7/63-20/7/63)-> Sx start for empirical intraabdominal infection
- anti TB drug : IRZE (19/7/63) * 2 months then IR until 9 months
- supplement : Vit B6 (50 ) ½*1 hs ,Vit D2 (20,000) 3 cap po weekly
Suspected
primary
immunodeficiency ??

DDx cause of disseminated TB in adolescent
1.Acquired :
Infection: HIV
Immunosuppressive drugs
Autoimmune diseases
Proliferative disorders : Lymphoma : no clues: (LDH 160+), no evidence thymoma
Anti-Interferon gamma autoantibody (anti-IFN-γ autoantibody)
2. Congenital (PID) :
hyper IgE syndrome, MSMD, CVID
Disseminated TB in adolescent male
Suggestion
1. Work up : CD3/CD4/CD8/CD19/CD56 level,
IgG/M/A/E level
2. Check HbA1c, ANA, LDH, anti-IFN-gamma

20/7/63
20 yr 8 mo
IgG (mg/dl)
1091.4
(548-1194)
IgM (mg/dl)
25 
(45-153)
IgA (mg/dl)
234
(78-322)
IgE (IU/mL)
679 
(<100)
20/7/63
20 yr 8 mo
ALC
(/ul)
335 
(1,600-2,400)
CD3
(/ul)
158 
(960-2,600)
CD4
(/ul)
104 
(540-1660)
CD8
(/ul)
47 
(270-930)
CD19
(/ul)
114 
(122-632)
CD56
(%)
47
(27-693)
Flow cytometry report Immunoglobulins
Immunologic work up
Anti-Gamma interferon 20/7/63
: 5.943 (Positive)

CBC 16/7/63 17/7/63 18/7/63 19/7/63 20/7/63 11/8/63 28/9/63
Hb 6.6 8 9.2 9.3 8.2 10.4 15.5 g/dL
Hct 22.2 25.4 28.4 29.2 25.2 33.1 46.5 %
MCV 88.8 86.7 85.8 85.1 85.7 90.4 94.5 Fl
RDW 21.8 19.9 17.5 17.34 17.1 22.2 14.1 %
WBC 11,870 12,820 10,720 8,630 6,520 5700 4980 /ul
Neutrophil 86 88.2 86.9 88 81.2 69 61.5 %
Lymphocyte 13 5.2 4.3 3.6 6.3 16.5 25.1 %
Monocyte 1 5.2 7.3 5.9 9.5 8.9 6.4 %
Eosinophil 0 0.5 0.9 1.6 2.1 4.4 3.7 %
Basophil 0 0.9 0.6 0.9 0.9 1.2 1.6 %
Platelets 454,000 447,000 335,000 323,000 261,000 453,000 263,000 /ul
ANC 10,208 11,300 9,320 7,590 6,300 3930 3,060
ALC 1,543 670 460 310 410 940 1,250
Case1: Progress note
Strat IRZE 1st admission 2nd admission

Case 2
A 14-years-old, Thai girl previous healthy ,unknown underlying
• CC: prolong fever 3 weeks PTA
• PI: 3 weeks PTA Prolong fever with Bilateral cervical lymphadenopathy
2 weeks PTA Rt hemiparesis with ataxia
• PH:
– Hx of Injected and enlarged tonsils whitish oral patch suspected infectious mononucleosis
– Chronic productive cough for 6 months
• FH:
– No family history of PID or unusual death
– No history of consanguinity

Present illness
1 month PTA
(10/12/2563)
3 weeks PTA
(28/12/2563)
1 week PTA
(10/01/2564)
ไข้ต่่ำเป็นๆหำยๆเป็นช่วงกลำงคืน เหงื่อออก
ไม่มีเบื่ออำหำร,น่ำหนักลด (BW 38 kg)
ไอเล็กน้อย เจ็บคอ ไม่มีกลืนล่ำบำก
ไม่มีนอนกรน ไม่มีคลื่นไส้อำเจียน
ไปตรวจที่รพชวินิจฉัยว่ำเป็นคออักเสบ
ได้ยำ Augmentin, Amoxycillin
อำกำรยังไม่ดีขึน
เริ่มรู้สึกอ่อนแรง ใช้ชีวิตประจ่ำวันได้
มำรดำสังเกตว่ำเริ่มเดินเซแต่ยังเดินเองได้
ไม่มีรองเท้ำหลุด จับปำกกำ ช้อนส้อมได้
ปกติ ยังมีไข้ต่่ำๆอยู่ตลอด เจ็บคอและไอ
ไข้สูงมำกขึน ไอ เจ็บคอและอ่อนแรงพอๆเดิม
ไม่มีผื่นตำมตัว ไปรักษำที่รพ.เอกชน
admit 10-14/1/64

• Vital sign: BT 36.5 C PR 80 bpm RR 12 /min BP 97/59 mmHg
• Body weight 35 kg (P3) Height 152 cm (P25-50) BMI 15.15 kg/m2
• Skin: no rash, no petechiae, not seen BCG scar
• HEENT: mild pale, anicteric sclerae, leukoplakia at tongue, no oral candidiasis
• Lung: clear, equal breath sound both lungs, no adventitious sound
• Heart: normal S1S2, no murmurs
• Abdomen: no distension, normoactive BS, soft, liver &spleen cannot be palpated
• Musculoskeletal: no deformities, no edema
• Lymph node: multiple left cervical LN 2x2 cm, well-defined, rubbery consistency,
movable, no soft tissue swelling,

• Neuro: alert, not well co-operate, E4VTM6
• CN II: pupil right 4 mm, left 3 mm RTLBE,
• CN III, IV, VI: eye deviate to right, not full EOM, limit saccadic gaze to left
• CN V: corneal reflex positive both eyes
• CN VII: left orbicularis oculi muscle weakness, cannot evaluate facial pals
• DTR: 3+ all
• Clonus: sustained clonus at right side
• Babinski: no response at right side, plantar flexion left side
• Sensation & Cerebellar signs: : cannot be evaluated
• Motor power : Rt arm grade 2 Rt leg grade 0 , Lt arm and leg 3+

CXR - multiple small pulmonary nodules (miliary pattern) diffuse in both lungs with small patchy opacities at
left apical lung
Bilateral cervical lymphadenopathy
(central necrotic nodes)
Pulmonary nodules diffuse both lung
Patchy opacities at superior segment LUL

- Multiple Rim enhancing hypodense lesion involve cortex and white matter of left frontal, parieto-temporal lobe,
both side of pons, left cerebellum with marked vasogenic edema, probably tuberculous abscess or tuberculoma
- Left uncal herniation , 0.6-cm midline shifting to the right

Case 2: Problem lists
Impression :
• 1. Miliary TB
• 2. Cervical lymphadenopathy suspected TB LN
• 3. Multiple brain abscess DDx TB
• Mx - Ceftriaxone 2 gm IV q12hr
- start IRZE (17/1/64) : INH 8.5 Mkday, Rifampicin 17 Mkday Pyrazinamide 35 Mkday,
Ethambutol → Ethionamide(250) 1.5 tab po bid (21 mg/kg/day) 22 MKday
- Dexamethasone 4 mg IV q6hr
- Dilantin 70 mg IV q8hr (6 mg/kg/day) prophylaxis post op
Suspected
primary
immunodeficiency ??

Case 2: Investigation
Chemistry
BUN 11 mg/dL
Creatinine 0.34 mg/dL
Na 132 mmol/L
K 3.3 mmol/L
Cl 103 mmol/L
HCO3 18 mmol/L
Calcium 8.3/9.5 mg/dL
Magnesium 0.8 mg/dL
Phosphate 3.3 mg/dL
LFT
AST 48 U/L
ALT 90 U/L
ALP 147 U/L
TB 3.55 mg/dL
DB 2.58 mg/dL
Albumin 2.5 g/dL
Globulin 3.7 g/dL
Culture 18/1/64
Tracheal suction G/S No organism
Tracheal suction C/S No growth
Tracheal suction AFB Positive 1+
PCR for MTBC Detected
C/S for TB Mycobacteriu
m tuberculos
is
LPA MTBC+,
sense I, R
CBC 18/1/64
Hb 10.6 g/dL
Hct 31.9 %
MCV 69.3 Fl
RDW 20.8 %
WBC 34,730 /ul
Neutrophil 93.8 %
Lymphocyte 2.8 %
Monocyte 0.2 %
Eosinophil 0 %
Basophil 3.2 %
Atyp Lymph - %
Platelets 538,000 /ul
ANC 32,577
ALC 972

CBC 18/1/64 20/1/64 25/1/64 8/2/64 17/2/64 5/3/64
Hb 10.6 9.8 10.6 11.2 13.8 12.3 g/dL
Hct 31.9 29.2 32.6 34.7 44.6 37.5 %
MCV 69.3 68.7 71.2 80.9 84.3 82.6 Fl
RDW 20.8 21.4 21.8 24.2 19.6 21.4 %
WBC 34,730 10,110 17,360 11,840 12,560 17,980 /ul
Neutrophil 93.8 80.9 82 76 67.6 83 %
Lymphocyte 2.8 8.7 4 9 20 9 %
Monocyte 0.2 9.9 3 6 7.8 1.1 %
Eosinophil 0 0.1 0 3 3.1 0.2 %
Basophil 3.2 0.4 0 2 1.5 0.16 %
Platelets 538,000 493,000 572,000 323,000 372,000 375,000 /ul
ANC 32,580 8180 8200 8990 8490 14,920
ALC 970 880 690 1060 2510 1620
Strat IRZE

Disseminated tuberculosis
• Affected organs ; pulmonary, lymph node, CNS
Plan for treatment
1) Anti-TB drugs
-Isoniazid (100) 3 tabs po hs (8.5 mg/kg/day)
-Rifampicin (300) 2 tabs po hs (17mg/kg/day)
-Pyrazinamide(500) 2.5 tabs po hs (35 mg/kg/day)
-Ethambutol → Ethionamide(250) 1.5 tab po bid (21 mg/kg/day)
-Vitamin B6 (50) 1 tab po OD
2) Corticosteroid is indicated
-Dexamethasone 4 mg IV q 6 hours (16mg/day max adult dose)
3) Side effects Monitoring
-Liver function test before initiation of treatment
-Observe rash and signs of hepatitis

Disseminated TB in adolescent female
• Normal adolescent female host
– Estrogen drives pro-inflammatory TH1-mediated
immune response while testosterone has been
found to inhibit the response
• Acquired immune deficiency
– HIV infection (50% of TB patient has HIV as
underlying disease)
– Anti IFN-γ autoantibody
• Primary Immune deficiency
– Mendelian susceptibility mycobacterium disease
– Combined immunodeficiency
– Chronic granulomatous disease
Investigations
-Flow cytometry -IgG, IgA, IgM, IgE
-DHR -Anti-IFN-gamma antibodies
DDx cause of disseminated TB in adolescent

25/1/64
14 yr 1 mo
8/2/64
14 yr 8 mo
IgG (mg/dl) 1318 
(698-1194)
907.3 ↔
(698-1194)
IgM (mg/dl)
169 
(59-99)
102 
(59-99)
IgA (mg/dl)
569 
(22-274)
361 
(22-274)
IgE (IU/mL)
1947 
(<200)
985 
(<200)
25/1/64
14 yr 1 mo
8/2/64
14 yr 8 mo
ALC
(/ul)
1,396 
(2,000-2,700)
1,497 
(2,000-2,700)
CD3
(/ul)
796 
(1,400-2,000)
988 
(1,400-2,000)
CD4
(/ul)
461 
(700-1,100)
569 
(700-1,100)
CD8
(/ul)
279 
(270-930)
419 
(270-930)
CD19
(/ul)
461 ↔
(300-500)
370 ↔
(300-500)
CD56
(%)
126 ↔
(59-1178)
240 ↔
(59-1178)
Flow cytometry report
Immunoglobulins
Case 2: immunologic work up
Anti-Gamma interferon 25/1/64
: 1.79 (Negative)
DHR 17/2/64
: normal
Genetic work up : pending

Case 1
20-year-old boy
Disseminated TB
(Sputum AFB positive , small bowel
and LN caseous granuloma )
No family history
Lymphopenia
Low number of T cell, B cell
High Ig E
Normal Ig G, Ig A
Low Ig M
Anti-gamma interferon
: 5.838 (Positive)
Case 2
14-year-old girl
Disseminated tuberculosis (lung,
brain, lymph node) with
tuberculoma with meningitis
No family history
No neutropenia ,Lymphopenia
Low number of T cell, B cell
High IgG , IgM ,Ig A and Ig E
Anti-gamma interferon
: 1.79 (Negative)
Anti-interferon-γ
autoantibodies

Mendelian susceptibility to mycobacterial disease
MSMD

J. Bustamante et al. Seminars in Immunology 2014; 26: 454-470.
A.K. Abbas et al.cellular and molecular immunology.9th ed.Chapter 21.
Mendelian susceptibility to mycobacterial disease: MSMD
• Rare inherited condition
• MSMD : patients are predisposed to severe disease caused by weakly virulent mycobacteria or
other intracellular pathogens including various bacterial, fungal, and viral species.
• Selective predisposition to clinical disease cause by weakly virulent mycobacteria
• Bacillus Calmette-Guerin: BCG
• non-tuberculous environmental mycobacteria : Mycobacterium avium, Mycobacterium kansasii,
and Mycobacterium fortuitum.
• Mycobacterial disease generally begins in childhood

• Vulnerable to more virulent Mycobacterium tuberculosis
• MSMD is strictly speaking a misnomer.
• The clinical phenotype extends beyond mycobacterial diseases.
• Salmonella: Typhoidal and non-typhoidal
• Intramacrophagic bacteria: listeriosis, nocardiosis, klebsiellosis
• Fungi: candidiasis, histoplasmosis, paracoccidiomycosis, coccidiomycosis
• Parasites: leishmaniasis, toxoplasmosis
• Viruses: CMV, HHV8, PRV-3, RSV, VZV
J. Bustamante et al. Seminars in Immunology 2014; 26: 454-470.
A.K. Abbas et al.cellular and molecular immunology.9th ed.Chapter 21.
Mendelian susceptibility to mycobacterial disease: MSMD

Interferon gamma–
IL12 signaling pathway
Macrophage/phagocyte/Dendritic cell
T cell /NK cell
1
Depending on the specific mutation,
inheritance of a disorder caused by mutation
in one of these genes can be AD,AR or X-linked.
Autoantibodies to interferon-γ itself can mimic
these genetic lesions, since they can potently
neutralize interferon-γ.
2
3
4
5
Holland SM et al. N Engl J Med 2017; 377: 1077-1091

Interferon gamma– IL12 signaling pathway
IL-12 signaling
- IL-12
- IL-12 receptor : (IL-12RB1 , IL-12RB2)
- TYK2 ,JAK2
- STAT4
Interferon-gamma signaling
- IFN-γ R1,R2
- JAK
- STAT 1
- NEMO
- GAF (interferon gamma activation factor)
NF-kB/NEMO signaling
- NEMO
- IKKa , IKKb
- NF-kB
Holland SM et al. N Engl J Med 2017; 377: 1077-1091

Genetic etiologies of MSMD
and
Clinical feature

• The first genetic etiology of MSMD was discovered in 1996. → IFNGR1 deficiency
• 13 MSMD-causing genes including
• 13 Autosomal mutations: IFNGR1, IFNGR2, STAT1(LOF), IL12B, IL12RB1, ISG15, IRF8, TYK2, RORC,
JAK1 (LOF), SPPL2a, IL-12RB2, and IL-23R genes
• 2 X-linked mutations: NEMO, CYBB
- Mutations in JAK1 and RORC have been described as responsible for syndromic MSMD.
• The high level of allelic heterogeneity has already led to the definition of 18 different disorders.
• These defects account for only about half the known MSMD cases.
J. Bustamante et al. Seminars in Immunology 2014; 26: 454–470
Ying W et al. Journal of Clinical Immunology (2019) 39:600–610

• The 13 gene products are physiologically related, as are involved in IFN-gamma-dependent
immunity.
• Impaired production of IFN-gamma: IL12B, IL12BR1, ISG15, IRF8, NEMO ,TYK2, RORC,
JAK1 (LOF), SPPL2a
• Impaired response of IFN-gamma: IFNGR1, IFNGR2, STAT1, IRF8, CYBB
• Disseminated mycobacterial infections have also been associated with
• GATA2 deficiency: MonoMAC syndrome
• Autoantibodies to IFN-gamma: acquired disease
• The identification of these genetic diseases has had clinical important.
• Rational treatment, preventive care, family screening, transplantation

Boisson-Dupuis et al. Immunol Rev 2015; 264(1): 103-120
Schematic diagram of the cooperation between phagocytes/dendritic cells and T lymphocytes/
NK cells during mycobacterial infection.

Genetic etiologies of MSMD.
The functional defects : complete (C) or partial (P).
The mutant proteins : may be (E+) , not expressed (E−),
not phosphorylated (P−)
unable to bind DNA (B−) on IFNs stimulation,
lost both these functions (P−B−).

Distribution of genetic disorders in MSMD patients with known etiologies
Most common
: IL12RB1 deficiency

Bousfiha A et al .2019 update of the IUIS phenotypical classification .J Clin Immunol (2020) 40:66–81

Clinical features
• Patients with mendelian susceptibility to mycobacterial disease often have onset of
infections in childhood, and BCG infection is common.
• Recessive complete deficiencies tend to present early in life.
• Recessive partial and dominant defects tend to present later in childhood or adulthood.
• X-linked recessive disorders (NEMO and CYBB mutations) : suspected in the setting of
multiple maternally related males with non-tuberculous mycobacterial infection.
• GATA2 deficiency and anti-interferon γ autoantibodies : disseminated NTM infection.
In adult onset
Wu UI, Holland SM. Lancet Infect Dis 2015; 15: 968- 980

Clinical features
Clinical manifestations of MSMD.
A. An enlarged left axillary lymph node with redness and tenderness
on the skin surface.
B. Groin abscess.
C. Lung infection on chest CT.
D. Bone destruction of the mandible

IFNGR deficiency
• Mutation gene: IFNGR1, IFNGR2
• IFNGR1 > IFNGR2
• Infection: BCG, Mycobacterial, Salmonella, listeriosis, viral infections
• Lab test: surface IFNGR, IFNGR function, 1st genetic etiology
increase serum interferon gamma
autosomal recessive
complete IFNGR1/R2
deficiency
Early-onset, disseminated, life-threatening with BCG or EM infections.
-severe form, 50% of these patients die before 10 years of age
Treatment : HSCT , anti-microbial
autosomal recessive
partial IFNGR1/R2
deficiency
-less severe
-mycobacterial infections caused by BCG or EM (M. avium, M. avium
complex, M. abcessus, M. szulgai).
anti-microbial, IFN-γ therapy
autosomal dominant
partial IFNGR1/R2
deficiency
- Less severe ,milder disease, good treatment response
• BCG or EM ; 80% of patients have mycobacterial osteomyelitis
anti-microbial and/or IFN-γ therapy
1st genetic etiology
Common form

STAT1 deficiency
• Inheritance for MSMD:
- AR complete STAT1 deficiency : life-threatening susceptibility to both mycobacteria and viruses
- AR partial STAT 1 deficiency : intracellular bacteria (BCG, M. avium, M. szulgai, Salmonella) and virus
(EBV, CMV and VZV) ; Partial impaired only IFN-gamma but not IFN-alpha/beta responses
- AD partial STAT1 deficiency: hypomorphic , loss of function
Infection: BCG, NTM, osteomyelitis, no unusual susceptibility to severe viral infections
• Treatment : Anti-microbial and IFN-γ therapy (good prognosis).

Infections in patients with deficiencies of IFN-γR and STAT1
Infections in patients with deficiencies of IFN-γR and STAT1
Infections in 115 patients with IFN-γR1 deficiencies (complete and partial)
21 patients with IFN-γR2 deficiencies (complete and partial)
17 reported patients with partial dominant STAT1 deficiency.
Some patients had multiple episodes of infectious diseases.
BCG, NTM

• Mutation gene:
• IL12RB1: B chain of IL12, IL23 receptor ; IL12B: p40 subunit of IL12, IL23
• Clinical phenocopies: IL12RB1 vs IL12B
• The most common genetic cause MSMD: IL12RB1 (AR complete IL12RB1 deficiency)
• Clinical very heterogenous (early death to asymptomatic)
• Infection: BCG, Mycobacterial infection, Salmonella (43%)
• Lab test:
• Reduce IFN gamma production, corrected by the additional of recombinant IL12
• IL12RB1: not express receptor on the surface, diminish pSTAT4 after IL12 stimulation
• IL12B: undetectable IL12 p40 subunit
• Treatment : prolonged & aggressive anti-microbial
and subcutaneous IFN-γ therapy
IL12RB1 - IL12B deficiency

IL12RB1 - IL12B deficiency
autosomal recessive
complete IL-12Rβ1
deficiency
Mycobacterial infections (TB ,NTM) , severe TB disease
recurrent BCG disease rare
invasive salmonellosis (40%)
autosomal recessive
complete IL-12p40
deficiency
BCG disease , TB , NTM
- Multiple mycobacterial infection –rare
- Salmonella and Klebsiella infection (25%) ,candida

Infections in patients with IL12RB1 and IL12p40 deficiency
Infections in patients with IL-12Rβ1 and IL-12p40 deficiencies Infections
180 patients with complete IL-12Rβ1 deficiency
50 reported patients with complete IL-12p40 deficiency.

Wu UI, Holland SM. Lancet Infect Dis 2015; 15: 968-980
Clinical manifestation

IRF-8 deficiency
• IRF8: Interferon regulatory factor 8
• Macrophages and dendritic cells need IRF8 for their ontogeny, maturation
• Transcription factor for IL-12 production in response to interferon-gamma
• AD IRF8 deficiency:
• Absence of monocyte and dendritic cells (CD11+, CD1c+ circulating dendritic cell)
• Impaired IL12 and IFN-gamma production
• Lab test:
PBMC+BCG → impaired IL12, IFN-gamma production, restored by the addition of IL12.
autosomal recessive
complete IRF8 deficiency
Multiple disseminated BCG disease , oral candidiasis,
severe respiratory infections
HSCT (curative treatment)
anti-microbial, antifungal
autosomal dominant
partial IRF8 deficiency
Mild recurrent episodes of disseminated BCG disease
without other infectious diseases
anti-microbial

• AR complete ISG15 deficiency (ISG15: Interferon-stimulated gene 15)
• Intracellular ubiquitin-like protein ,antiviral defense through ISGylation of
various proteins
• Extracellular cytokine secrete by granulocytes, monocytes and lymphocytes to
induce interferon-gamma production by T cells and NK cells
• Infection: BCG, mycobacterial infection
epileptic seizure , intracranial calcification
• Lab test:
PBMC+BCG+IL-12 → impaired IFN-r production, restored by the addition of
recombinant ISG15.
• Treatment : anti-microbial and subcutaneous IFN-γ therapy
ISG15 deficiency

• Mutation gene: X-linked IKK-γ gene (IKBKG)
• Inheritance for MSMD: X-linked recessive
• somatic feature : anhidrotic ectodermal dysplasia (impair regulate development of
skin, hair and teeth): hypodontia, sparse hair, abnormal hair whorls
• Infection: Non-tuberculous mycobacterial infection, M. avium ,encapsulated bacteria
,herpes viruses, Pneumocystis jirovecii.
Most common : invasive pneumococcal disease, Invasive Hib infection
• Lab test: increase IgM, low IgA or IgG
• Treatment : anti-microbial and subcutaneous IFN-γ therapy
NEMO deficiency

• Mutation gene: CYBB (gp91phox), Q231P, T178P
• Inheritance for MSMD: X-linked recessive
• Selective functional impairment of superoxide production limited to
monocyte-derived macrophages and B cells
• Normal production of IL12, Interferon-gamma
• Infection: Staphylococcus, Aspergillus limited BCG susceptibility phenotype
• Lab test: DHR to measure intracellular respiratory burst in macrophages
and B cells
CYBB deficiency

X-linked recessive

• GATA2: transcription factor for early hemopoietic, lymphatic and vascular
development
• Monocytopenia with M. avium complex syndrome: MonoMAC
• Decrease or absent circulating monocytes, dendritic cells, NK cells, B cells →
impaired cytokine production
• Onset: childhood to adulthood (3-80 years)
• Infection: HPV(70%), disseminated non-tuberculous mycobacterial infection,
disseminated histoplasmosis, cryptococcal meningitis, invasive aspergillosis,
severe clostridium difficile infection.
GATA2 deficiency

Late onset

Clinical
manifestation

• Functional studies of IL12/Interferon-gamma axis
• Genotyping is the gold standard for the diagnosis of genetic defects.
• Molecular assays are not available in all clinical settings.
• Diagnostic clues:
• Age at onset
• Sex
• Pattern of inheritance
• Pathological features
• Concomitant infections
• complications
Diagnosis

Inherited and acquired immunodeficiencies
underlying tuberculosis in childhood

Intramacrophage pathogen : salmonella
Acquired and inherited conditions with
mycobacterial susceptibility to
BCG, NTM, or Mycobacterium tuberculosis (TB)

Differential diagnosis
Mycobacterial susceptibility infection
PID
Inherited ID
Acquired ID MSMD
• HIV infection, hairy cell leukemia, individuals taking specific immunosuppressive therapies.
• medication : TNF α blockers predispose individuals to reactivation of tuberculosis, and NTM infections.
Anti-cytokine antibodies conferring a predisposition to mycobacterial diseases : adult onset
1.Anti IFN-γ autoantibodies : acquired phenocopy of inborn errors of IFN-γ.
Mostly in NTM infection , Salmonella, Cryptococcus neoformans,
Histoplasma capsulatum, Penicillium marneffei, and varicella zoster virus.
Associated HLA-DRB1* 16:02 , HLA-DQB1*05:02
2.Anti TNFα- autoantibodies : Therapeutic TNFα-blocking antibodies : favor mycobacterial disease in JIA and
pediatric inflammatory bowel disease

Rosenthal et al. Cureus 11(6). 2019 : e4967
case which disseminated TB was found in healthy
adolescent, female patient, and to explore the effects
of pubertal hormonal changes on the immune system.
hormonal changes of estrogen and testosterone
associated with puberty may influence the pathogenes
is of active TB.
Pathogenesis of disseminated TB : unknown
A 16-year-old girl with previous healthy
CC : dry cough with weight loss 9 kg the past 3 months PI : She
also endorsed a three-month history of amenorrhea.
patient denied hemoptysis, fevers, night sweats, sick contacts.
PE: febrile (102.8F) and RR 56 pbm with normal SpO2 on RA
BW 24 kg Ht 130 cm.
lung : decreased breath sounds bilaterally and rhonchi BL
Chest X-ray: extensive bilateral nodular opacities with a cavitary
lesion in the upper right lung.
Chest CT : extensive nodules and consolidations throughout
bilateral lungs with large bilateral upper lobe cavitations.
Labs : Hb 8.2 MCV 76 WBC 21,800/mcL (Neu 81%),
CRP : 23.8 mg/dl.
Sputum AFB : positive.
Impression : Pulmonary tuberculosis

Treatment :
Start : high dose isoniazid (INH), ethambutol, rifampin, levofloxacin, steroids,
Due to amenorrhea and the patient’s failure to thrive,
Abdominal and pelvic CT : calcified granulomas in the spleen and liver, a cystic mass in the right adnexa, and thickening of t
he ileum; findings indicative of disseminated TB.
Progression
On hospital D4 : Patient exhibited sluggish pupillary responses.
MRI (brain) : mild ventriculomegaly, thickening of the meninges, and focal areas of demyelination in the left parietal and
frontal lobes, consistent with central nervous system (CNS) TB.
Sputum cultures : high resistance to INH (>2) and low resistance to streptomycin (>32).
Mx : INH was continued due to its ability to penetrate the blood-brain barrier to target the CNS involvement.
With continued treatment, her AFB smears&cultures were found to be negative in blood, urine, CSF and BM.

Proposed : Estrogen has been shown in vitro to drive the pro-inflammatory TH1-mediated immune responses
while testosterone has been found to inhibit these responses.
Androgens, alterations in the cortisol to DHEA ratio are associated with disturbances in concentrations of
interferon-gamma, a key cytokine involved in TB containment.
Chronic malnutrition :
Decrease dendritic cell activity in mice ,
Decreased T helper type 1 (Th1) activation, there is insufficient IL-12 and IFN-gamma to stimulate macrophages.
Failure of the host immune system to adequately contain the TB.

• Adult onset, Female (outside Asia)
• Infection:
Acquired susceptibility to NTM infections and other opportunistic infections
(Salmonella , Penicillium marneffei, Histoplasma, Cryptococcus, Burkholderia pseudomallei
cytomegalovirus, and varicella-zoster reactivation)
• Lab test: high titer, neutralizing anti-interferon antibodies,
normal CD4+T cell, monocyte numbers, IFNGR and IL12R
• HLA-DRB1*16:02 and DQB1*05:02 – were associated with disease
• When to test Anti- IFN-r autoantibody :
NTM infection with reactive dermatosis (sweet syndrome , AGEP, erythema nodosum)
Anti-interferon gamma autoantibodies
Kent Mun Loh et al.CORRESPONDENCE .cid 2020:71 (1 October)

Phoompoung P. et al. PLos one 2017; 24: 12(4):e0176342
Case control study
Patients with NTM diseases who were diagnosed and treated at Siriraj Hospital, Bangkok, Thailand.
Anti-IFN autoantibody was detected by enzyme-linked immunosorbent assay (ELISA) method.
Cases : 70 patients with NTM diseases and detectable anti IFN- γ autoantibody.
Controls : 70 patient randomly selected from those with undetectable anti IFN- γ autoantibody.
Objective :
Univariate & multivariate analyses were performed to identify independent risk factors for this syndrome.

Phoompoung P. et al. PLos one 2017; 24: 12(4):e0176342
Result
Mycobacterial abscessus was the most common NTM pathogen found in both groups (72.9% in cases VS 41.4% in control).
Disseminated NTM disease was significantly more common in cases (92.9%) than controls (14.3%, p<0.001).
Binary logistic regression analysis showed that
Previous OIs (adjusted OR14.87), birthplace outside Central region (adjusted OR 19.19),
Lack of comorbidities lead to immunosuppression (HIV infection or DM)(adjusted OR 23.68),
and presence of HLA DRB1*15/16 (adjusted OR 153.28) were
independent factors
associated syndrome.
Conclusion
Patients with NTM disease associated with anti IFN- γ autoantibody are previously healthy and HIV negative.
Most of these patients presented with disseminated NTM disease with generalized lymphadenitis and reactive skin lesions.
Factors associated with detectable anti IFN- γ autoantibody : HLA-DRB1 and DQB1 alleles, and history of previous OIs
in patients without comorbidity that leads to immunosuppression.

Hong GH et al. anti-interferon-γ autoantibody-associated immunodeficiency syndrome in Thailand and the US. Clin Infect Dis 2020:71.
Isolated organisms at presentation in Thailand and the United States
M.abscessus
M.avium complex
91% of US patients were of Southeast Asian;
female predominance (91%) in US than Thai (64%) pts.
Mycobacterium abscessus (34%) :
most common NTM infection in Thailand
Mycobacterium avium complex (83%) :
most common NTM infection in US

Hong GH et al. anti-interferon-γ autoantibody-associated immunodeficiency syndrome in Thailand and the US. Clin Infect Dis 2020:71.
Sites of infections at presentation in Thailand
and the United States
Site of infections in anti-IFN-r autoantibodies
- Thailand : Skin infection
- US : bone , lung CNS system
Most common cause of death in Thailand
- infection
Treatment
- Cyclophosphamide
- Rituximab therapy
Rituximab and cyclophosphamide
significantly lowered autoantibody titers.
effectively reduce autoantibody titers and improve IFN-r signaling.

Koizumi Y et al. anti-interferon-γ autoantibody-disseminated NTM infection. Clin Infect Dis 2020:1-3.
• Specific treatment for IFN-γ autoantibodies–associated NTM infection is not codified
and required prolonged, multiple-drug regimens.
• The median treatment duration: 31 (IQR 22.8–60.0) months.
• The use of azithromycin suppressive therapy, assuming the risk/ benefit balance
including the possibility of NTM or macrolide resistant strain selection.
• should be considered for persisting high levels of neutralizing antibodies
• Use of immunomodulation strategies is still debated

Koizumi Y et al. anti-interferon-γ autoantibody-disseminated NTM infection. Clin Infect Dis 2020:1-3.
• IFN-γ administration was invalidated by the
autoimmune-driven inhibitory.
• Rituximab has been recently associated with clinical
response and decrease in IFN-γ autoantibody levels as
well as neutralizing ability.
• Treatment strategy
1.Recovery of cellular immunity
2.Elimination of anti-cytokine autoantibodies
3.Suppression of wasting inflammatory reaction
Corticosteroid Decrease titers of neutralizing autoantibodies
Cyclophosphamide adjunctive therapy regimen for refractory to conventional
antimycobacterial therapies
Rituximab Refractory disseminated NTM infection
Daratumumab Disseminated NTM infection refractory to other agents

PID
Inherited ID
Acquired ID MSMD
• Healthy individuals ( Especially for the airways : Isolated pulmonary NTM infection) : adult onset
- Pts with structural lung abnormalities :
COPD, bronchiectasis, emphysema, previous TB, pulmonary alveolar proteinosis, alpha-1-antitrypsin deficiency
- Cystic fibrosis
- Primary ciliary dyskinesia
- Lady Windermere syndrome
• Immunocompetent : children onset
- Present as isolated cervical lymphadenitis or isolated pulmonary disease
- To date, neither CFTR mutations nor other primary immune defects have been often noted in these patients.

PID
Inherited ID
Acquired ID MSMD
PID with T-cell deficiency
Severe combined immunodeficiency diseases (SCID) various infectious diseases (viral, bacterial, fungal, or parasitic) in
the first few months of life. Disseminated BCG infection
Combined immunodeficiency (CID), NTM infection
ZAP-70 deficiency BCG-itis , NTM infection
Autosomal dominant GATA2 deficiency immunodeficiency with marked susceptibility to HPVs
mycobacteria (non-tuberculous and tuberculous)
defect dendritic cell, monocyte, B cell, and NK cell
Chronic granulomatous disease (CGD) pyogenic bacterial & fungal infections, (S.aureus , Aspergillus ,
mycobacterial infections).
Anhidrotic ectodermal dysplasia with
immunodeficiency (EDA-ID)
ectodermal dysplasia , invasive pyogenic bacteria, NTM, TB,
parasites, viruses, and fungi .

PID
Inherited ID
Acquired ID MSMD
X-linked recessive CD40L deficiency (X-HIGM) recurrent bacterial infections, OI with PCP & Cryptosporidium species,
localized and disseminated BCG ,NTM ,TB infection
Autosomal recessive STAT1 deficiency Milder to severe, life threatening of mycobacterial and viral infection
Autosomal recessive IRF8 deficiency Life-threatening disorder combine fungal and mycobacterial infections
, myeloproliferation and an absence of monocytes and dendritic cells.
BCG-osis, oral candidiasis.
Autosomal recessive TYK2 deficiency disseminated mycobacterial and viral diseases.
BCG-osis, severe abdominal TB, and miliary TB

PID
Inherited ID
Acquired ID MSMD
IFN-γR deficiencies Very severe ,BCG and NTM or TB infection
Autosomal dominant STAT1 deficiency BCGosis ,NTM, TB infection
X-linked recessive gp91phox deficiency mycobacterial diseases due to impairment of respiratory burst in macrophage.
Autosomal dominant IRF8 deficiency recurrent episodes of mycobacterial disease caused by BCG
defect dendritic cell, monocyte, granulocyte
X-linked recessive NEMO deficiency mycobacterial diseases (BCG and NTM), Invasive Hemophilus influenza typeB
infection
Autosomal recessive IL-12p40 and
IL-12Rβ1 deficiencies
Various clinical , BCG ,NTM,TB infection ,salmonellosis (30-40%) , candidiasis
Autosomal recessive ISG15 deficiency BCG disease , intracranial calcification

Clinical diseases allelic with MSMD at the NEMO, CYBB, STAT1 and IRF8 loci

Investigation
• Exclude HIV infection
• Routine Evaluation of Immunological Function : lymphocyte subsets, Immunoglobulins G, A, M,
and NADPH oxidase activity in neutrophils (DHR)
• Functional Evaluation of the IL-12/IFN-γ Pathway
- Flow cytometry detection of CD119 and CD212
(Production of IFN-γ in whole blood after stimulation with medium alone, LPS, or LPS plus IL-12)
The first row shows histograms of IL12Rβ1 expression in a healthy individual (left)
and a patient (right).
The second row shows expression of IFN-γR1 protein in a healthy individual (left),
patient with decreased expression (middle),
patient with no expression (right)
CD 212 : IL12Rβ1 expression
CD 119 : IFN-γR1 protein
Flow cytometric detection of IL12RB1 and IFNGR1 : rapid diagnosis

Investigation
• Gene Sequencing and Analysis : Next-generation sequencing (NGS)
• Phosphorylated STAT1 Protein Detection by Western Blotting
Reduced IFN-γ induced phosphorylation of STAT1.
PBMCs were not stimulated (PBS) or were stimulated with IFN-γ
IL12RB1 gene
IFN-γR1 gene
IFN-γR2 gene
STAT1 genes

Stepwise approach to diagnosis of patients with
disseminated non-tuberculous mycobacterial (DNTM) infection
X-linked Adult onset

Treatment
Early onset late onset
GATA 2 deficiency :
HSCT, Anti-microbial ,
IFN-gamma
-Anti-IFN-gamma autoantibodies :
Anti-microbial
if severe/refractory :
immunomodulation agent
- Corticosteroid
- Cyclophosphamide
- Rituximab
HSCT :
IFN-gamma R1 , IFN-gamma R2 (complete deficiency)
Anti-microbial :
IFN-gamma R1 , IFN-gamma R2 (complete deficiency)
IFN-gamma (rhIFN-γ therapy ) :
IFN-gamma R1 (partial deficiency)
IL-12 and IL-12R deficiency
STAT1 LOF
rhIFN-γ therapy is effective and improves prognosis, particularly in patients with IL12RB1 deficiency

Prognosis
a. Kaplan-Meier estimate of survival for patients with MSMD treated with (solid line) or without (dashed line) IFN-γ
(log-rank χ20.998; P = 0.31).
b. Kaplan-Meier estimate of survival for patients with IL12RB1 treated with (solid line) or without (dashed line) IFN-γ
(log rank χ2 5.247; P = 0.022)
The median survival time was 26 months (range, 5 to 173 months).
MSMD IL12RB1 deficiency

Mendelian susceptibility to mycobacterial diseases

Mendelian susceptibility to mycobacterial diseases

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