Wang Xiaochuan Children’s Hospital Immunodeficiency diseases Wang, Xiaochuan Department of Clinical Immunology, Children’s Hospital of Fudan University

Wang Xiaochuan Children’s Hospital

Immunodeficiency diseases

Wang, Xiaochuan

Department of Clinical Immunology, Children’s Hospital of Fudan University


Pathogens

Environment Material

Immunity

Infectious Immunity

Allergy

Tumor Immunity

Autoimmune Disease

PID


Immunocompromised Host

• Individual who has one or more defects in the body’s natural defense mechanisms which are sufficiently severe to predispose the host to life- threatening infection and high risk of autoimmune diseases, allergy and malignancy

• Primary - PID, damage to anatomical barriers• Secondary - infection, tumor, drug, others• Physiology- Infants, aged


Characteristics of Immunoglobulines

IgG IgM IgA IgD IgE

Serum Con. (mg/dl) 1200 120 200 3 0.01

Percentage 70-80 5-10 10-15 <1 <0.01

Half life(days) 21 5 7 2.8 2.3

Distribution (%) 45 80 45 75 50

Quantity (mg/kg) 1150 49 230 1.5 0.04

Synthesis(mg/kg/D)

35 7 25 0.4 0.02

Transport through placenta

+ - - - -


Development of Immunoglobulin

IgG from motherIgG of infant

6Mbirth

100%IgG level of Infant


Age dependent changes of serum Igs levels(g/L)

Ages IgG IgA IgM

Neonate 6.46-17.74 0.004-0.017 0.05-0.27

1m- 2.75-7.50 0.05-0.60 0.10-0.70

4m- 3.70-8.30 0.14-0.50 0.33-1.25

7m- 3.50-8.90 0.06-0.54 0.36-1.20

1y- 5.52-11.46 0.06-0.74 0.60-2.12

3y- 4.95-12.74 0.33-0.89 0.65-2.01

7y- 6.09-12.85 0.52-2.16 0.67-2.46

12y- 6.98-14.26 0.92-2.50 0.56-2.18

15-18y 7.54-16.02 0.89-3.24 0.72-2.28


Schematic diagram of the exposure of microorganism during early life

fetus Full tern 6M Day care

pathogens

probiotics


Period of susceptible children

prematureFull term

6M Day care


Management

• Exclusion of PID

• Clinical features– Frequency of infection– Severity– Complications

• Follow up


Management

• General medical care (prevention 、 nutrition 、 exercise)

• Complication Treatment

• Medication – Antibiotics– Immune regulator– Immunizations


(Primary Immunodeficiency Disease, )


Primary Immunodeficiency Disease

• A group of disorders characterized by an impaired ability to produce normal immune response. Most of these disorders are cased by mutations in genes involved in the development and function of immune organs, cells, and molecules.

• • Clinical features ： Recurrent infection, high risk of

autoimmune diseases, allergy and malignancy


50%

20%

10%

18%2%

Antibody

ComplementPhagocyte

Cell mediated

Combined


Predictive patients number of PID in Shanghai

• X-Linked Agammaglobulinemia (XLA) 1/ 100,000

• Selective IgA Deficiency 1/10000 • Severe Combined Immunodeficiency

(SCID) 1/1,000,000• Chronic Granulomatous Disease (CGD)

1/1,000,000

100

500

10

10


Classification (old)

• Antibody(B cell) deficiency

• T cell deficiency

• Combined immunodeficiency

• Phagocyte deficiency

• Complement deficiency


Classification(new)

• Combined Immunodeficiency • Predominantly antibody deficiency• Predominantly T-cell deficiency• Immunodeficiency syndromes

• Phagocyte deficiency• Complement deficiency

• Others


Up to 2007 more then 200 kinds of

PID reported

1. 联合免疫缺陷(1) 无 T 有 B (a)X- 连锁 (γc 缺陷 )(b) 常染色体隐性 (Jak3 缺陷 )(c)IL7R 缺陷(d)CD45 缺陷(2) 无 T 无 B(a)RAG1/2 缺陷(b)Artemis 缺陷(c) 腺苷脱氨酶 (ADA) 缺陷(d) 网状组织发育不良(3)Omenn 综合征(4)X- 连锁高 IgM 综合征(5)CD40 缺陷(6) 嘌呤核苷磷酸化酶 (PNP) 缺陷(7)MHC Ⅱ 类缺陷(8)CD3γ 或 CD3ε 缺陷(9)CD8 缺陷(10)ZAP-70 缺陷(11)TAP-1 缺陷(12)TAP-2 缺陷(13)WHN 缺陷 2. 抗体缺损为主的免疫缺陷(1)X- 连锁无丙种球蛋白血症(2) 常染色体隐性无丙种球蛋白血症(3)Ig 重链基因缺失(4)κ 链缺陷(5) 选择性 Ig 缺陷(a) IgG 亚类缺陷(b) IgA 缺陷(6)Ig 水平正常的抗体缺陷(7) 常见变异型免疫缺陷(8) 婴儿暂时性低丙种球蛋白血症(9)AID 缺陷 3. 其它确认的免疫缺陷综合征(1)Wiskott-Aldrich 综合征(2) 共济失调毛细血管扩张(3)Nijmegen breakage

(4) 第 3 、 4 咽囊综合征 (DiGeorge anomaly)

(5) 伴有白化病的免疫缺陷(a) Chediak Higashi 综合征(b) Griscelli 综合征(6)x- 连锁淋巴增殖综合征(7) 家族嗜血细胞性淋巴组织病(8)X- 连锁免疫调节异常、多种内分泌病、

肠病综合征(9) 自身免疫性多种内分泌病和外胚层发

育不良(10) X- 连锁免疫缺陷和外胚层发育不良 4. 补体缺陷C1q,C1r,C4,C2,C3,C5,C6,C7,C8α ，

C8β ， C9 ， C1 抑制物， I 因子，H 因子， D 因子，备解素等 16种成分各自的缺陷

5. 吞噬细胞数量和 / 或功能缺陷(1) 严重先天性嗜中性粒细胞减少症(2) 循环嗜中性粒细胞减少症(3)X- 连锁嗜中性粒细胞减少症(4) 白细胞粘附缺损 1(5) 白细胞粘附缺损 2(6) Rac-2GTP 酶缺陷(7) 幼年型局限性牙周炎(8) 特异性颗粒缺陷(9) Schwachman-Diamond 综合征(10) 慢性肉芽肿病 (CGD)(a)X- 连锁 CGD( 细胞色素 b 的 91kD

链缺陷 )(b) 常染色体隐性遗传 ( 细胞色素 b 的

22kD 链缺陷或胞液因子的 p47或 p67 缺陷 )

(11) 嗜中性粒细胞葡萄糖 -6- 磷酸脱氢酶 (G6PD) 缺陷

(12) 髓过氧化酶缺陷(13) 白细胞分枝杆菌缺陷(a) IFN-γ 受体缺陷(b) STAT-1 缺陷(c) IL-12 受体缺陷(d) IL-12 缺陷

6. 其它原发性免疫缺陷病(1) 原发性 CD4T 细胞缺陷(2)IL-2 缺陷(3) 多种细胞因子缺陷(4) 伴有或不伴有肌病的信号转导 (transduction) 缺陷(5) 伴肌病的钙流通缺陷


Case • 7-year-old Male ， with 6 years history of recurrent

coughing, fever, joints swollen and painful for 5 years.• The first onset of fever and coughing was at 10 months

of age. Fever, coughing and left knee painful with move obstruction at 1 years and half age. After then on, the recurrent high fever, coughing and processing left knee functional obstruction exhibited every 2-3 months. Sometimes the symptoms were released by penicillin. The JRA, ankylosing spondylitis, rheumatic pneumonia were diagnosed successively and treatment with a series medicines.

• A mother’s brother died as reccurent pnumonia and septicemia in infancy.


Case (continue)

• Physical examination ： T 39-40°C ， malnutrition, small lymph nodes, absent tonsil

• He had pneumonia and hepatosplenomegaly. Bilateral elbows, wrists, knees and ankle were swelling with tender, muscular atrophy.


Case (continue)–Lab investigation

• RF negative , ESR ： 19mm/h, CRP ： positive ANA negative ， ENA negative, blood culture ：negative

• CD3: 83.77%, CD4: 31.89%, CD8: 46.98%, CD19: 0%.

• IgG: 0.1g/L; IgA: 0.02g/L; IgM: 0.03g/L; IgE: 32IU/ml 。 CH50 ： 90U/ml; C3: 189mg/dl

• X-ray ： periarticular soft-tissue swelling, periarticular osteopenia, and erosions with subluxation of the joint. Knees were deformation.


Characteristics

• Male, onset at 10 months

• Recurrent infection

• Recurrent arthritis

• Deceased serum Igs

• Absence of circulating B cell


Case continue (Diagnosis)

• Primary Immunodeficiency disease(X-linked agammaglobulinemia)

• Juvenal Idiopathic Arthritis

• Pneumonia

• Diarrhea

• Malnutrition


Antibody (B cell) Immunodeficiency

• Hypogammaglobulinemia– X-linked agammaglobulinemia (XLA)– Transient Hypogammaglobulinemia– Common variable immunodeficiency disease

(CVID)

• Selective Ig deficiency – selective Ig A deficiency– selective Ig M deficiency– selective Ig G subclass deficiency


Clinical features of antibody immunodeficiency

• Onset during 6 － 12 months of age• Recurrent Pyogenic bacterial infection

(encapsulated invasive bacteria)• Pneumonia, media otitis, sinusitis, skin

infection, meningitis, sepsis• Rare fungal, viral infection (but entericvirus)• High risk of allergy and autoimmune

diseases


X-linked agammaglobulinemia

(XLA; Bruton syndrom)• Gene defect ：

– Xq22 coded B cell tyrosin kinase ( Btk ) defect, XL

• Mechanism:– B cell signal pass way disorder, development of

B cell impaired


Clinical manifestations of XLA(1)

• Onset at 6-12 month of age, male • Recurrent bacterial infection• Pyogenic encapsulated bacteria:

– Streptococcus, Pneumoniae, Haemophilus influenzae, Staphylococcus aureus

• Recurrent upper and lower respiratory infections, Pneumonia, media otitis, sinusitis, skin infection, meningitis, sepsis

• 1/3 untreated patients with arthritis


Clinical features of XLA(2)

• Physical examination ：– Failure to thrive, small or absent tonsil,

peripheral lymph nodes

• Lab investigation ： – IgG<2g/L, IgM 、 IgA 、 IgE reduced – Peripheral B cells absence, presence of pre or

pro B cells in bone marrow– Normal T cell counts and function – Reduced monocyte BTK expression


Common variable immunodeficiency disease(CVID)

• Pathogenesis: unclear


Clinical manifestations

• Onset at any age, male and female • Recurrent Pyogenic bacterial infection• Higher risk for autoimmune diseases • Physical examination:

– Part of patients tonsil and lymph node enlarge

• Lab investigation: – IgG<3 g/L, most deficient in IgM 、 IgA 、 IgD 、 IgE– Most have near normal peripheral B cell– T cell numbers and function may be abnormal – Normal monocyte BTK expression


Clinical features of combined immunodeficiency

• Onset age at early infants(4 － 5 months) • Recurrent infection with fungi, virus, bacteria,

mycobacterium, protozoa • Opportunistic infections • Poor prognosis, early infant deaths • Severe infection after live virus vaccine and BCG • GVHD after blood transfusion • High risk of malignancy


X-linked Hyper IgM syndrome (HIGM)

• Gene defect: T cell CD40 ligand defect, Chromosomal location Xq24 － 27, XL

• Pathogenesis: Failure of B cell isotype switch


Clinical manifestations

• Age of onset: first or second year of life• Male • Recurrent bacterial infections, other

opportunistic infections include cytomegalovirus, mycobacteria, pneumocystis carinii

• Lab investigation: Normal or elevated IgM level, decreased other Igs.


Pre B cell Immature B cellIgM (IgD)

Mature B cell Igs

Isotype switch

HIGM

patient T 、 B cell cytokines failure of Ig isotype switch （ IL-2 , 4, 10 ）

normal T cells ＋ patient B cells ＋ cytokines Ig isotype seitch

HIGM


Immunodeficiency syndromes


Wiskott-Aldrich Syndrome

• Gene defect: Xp11.22, Wiskott-Aldrich syndrome protein(WASp), XL

• Clinical manifestations: X-linked, male onset at early infant, eczema, thrombocytopenia, recurrent infection lymphomas, autoimmune disease

• Lab investigation: decreased IgM; often increased IgA and IgE


Ataxia-telangiectasia

• Gene defect ： mutation in A-T gene (ATM), AR

• Clinical manifestations– Ataxia– Telangiectasia – Recurrent infections– Malignancies– X-ray sensitivity


DiGeorge anomaly

• Genetic defect: located at 22q11, AR• Contiguous gene syndrome that affect

multiple organs during early embryogenesis– Thymic hypoplasia– Hypocalcaemia– Cardiac abnormalities– Cleft palate– Abnormal facies


Chronic granulomatous disease(CGD)

• Genetic defect:– gp 91 phox, XL– p22 phox; p47 phox; p67 phox, AR

• 2/3 onset before 1 year, most under 6 months of age

• Skin infection and abscess


Non classical immunodeficiency diseases


IL-12RB1 deficiency

• Case: – 1 years old girl with BCG infection from first

month after got BCG vaccine. – With very limited effects with the anti-

tuberculosis therapy– Immunology evaluation is normal


IL-12RB1 gene mutation

Intron 15 (+2) T>G mutation

Intron 15 (+2) T/G carrier

Intron 15 (+2) T/G carrier


IFN/IL-12 pathway

Macrophage

IL-12 R

IL-12

IFN-

p40p35

T/NK cell

12

IFN-R

Other factors, e.g., TNF-

IFN-R

STAT4

STAT1


It is now clear that most, if not all individuals, suffer from at least one PID, the clinical expression of which depends on exposure to ad hoc environmental factors, infectious or otherwise.

Casanova JL, Abel L. SCIENCE 2007(317): 617-619


Treatment

• General management

• Immunoglobulin

• Replacement therapy

• Transplantation, others


General management

• Diet

• Avoidance of pathogens (“germ-free” care)

• Antibiotics– Use in acute illness– Prophylactic

• Avoid whole blood transfusion in combined immunodeficiency disorder

• Avoid live virus vaccines and BCG


Immunoglobulin replacement

• Treatment of severe antibody disorders

• Intramuscular – 0.1g/kg/m

• Intravenous– 0.4-0.6g/kg/m


Immunoglobulin replacement adverse effects

• Local reactions: intramuscular gammaglobulin, tenderness, abscesses, fibrosis

• Systemic reaction: Fever, chills, nausea, vomiting; anaphylactic reaction are unusual


Specific treatment for cellular deficiency

• Bone marrow transplantation

• Replacement therapy– Enzyme replacement– Gene therapy– Thymic hormones– Cytokines

• Fetal thymus transplantation


Specific treatment of phagocytic disorders

• Interferon gamma for CGD

• Granulocyte transfusion


Thank you for your attention

Documents

Wang Xiaochuan Children’s Hospital Immunodeficiency diseases Wang, Xiaochuan Department of Clinical Immunology, Children’s Hospital of Fudan University