Wang Xiaochuan Children’s Hospital
Immunodeficiency diseases
Wang,Xiaochuan
Department of Clinical Immunology,
Children’s Hospital of Fudan University
Wang Xiaochuan Children’s Hospital
Pathogens
Environment Material
Immunity
Infectious
Immunity
Allergy
Tumor
Immunity
Autoimmune Disease
PID
Wang Xiaochuan Children’s Hospital
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
? Primary - PID,damage to anatomical barriers
? Secondary - infection,tumor,drug,others
? Physiology- Infants,aged
Wang Xiaochuan Children’s Hospital
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
+ - - - -
Wang Xiaochuan Children’s Hospital
Development of Immunoglobulin
IgG from mother IgG of infant
6Mbirth
100%
IgG level of Infant
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
Schematic diagram of the exposure
of microorganism during early life
fetus Full tern 6M Day care
pathogens
probiotics
Wang Xiaochuan Children’s Hospital
Period of susceptible children
premature
Full term
6M Day care
Wang Xiaochuan Children’s Hospital
Management
? Exclusion of PID
? Clinical features
– Frequency of infection
– Severity
– Complications
? Follow up
Wang Xiaochuan Children’s Hospital
Management
? General medical care (prevention,nutrition、
exercise)
? Complication Treatment
? Medication
– Antibiotics
– Immune regulator
– Immunizations
Wang Xiaochuan Children’s Hospital
(Primary Immunodeficiency
Disease,)
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
50%
20%
10%
18% 2%
Antibody
ComplementPhagocyte
Cell mediated
Combined
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
Classification (old)
? Antibody(B cell) deficiency
? T cell deficiency
? Combined immunodeficiency
? Phagocyte deficiency
? Complement deficiency
Wang Xiaochuan Children’s Hospital
Classification(new)
? Combined Immunodeficiency
? Predominantly antibody deficiency
? Predominantly T-cell deficiency
? Immunodeficiency syndromes
? Phagocyte deficiency
? Complement deficiency
? Others
Wang Xiaochuan Children’s Hospital
Up to 2001 more
then 100 kinds of
reported PID
1,联合免疫缺陷
(1) 无 T有 B
(a)X-连锁 (γ c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
Wang Xiaochuan Children’s Hospital
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.
Wang Xiaochuan Children’s Hospital
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.
Wang Xiaochuan Children’s Hospital
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.
Wang Xiaochuan Children’s Hospital
Characteristics
? Male,onset at 10 months
? Recurrent infection
? Recurrent arthritis
? Deceased serum Igs
? Absence of circulating B cell
Wang Xiaochuan Children’s Hospital
Case continue (Diagnosis)
? Primary Immunodeficiency disease(X-
linked agammaglobulinemia)
? Juvenal Idiopathic Arthritis
? Pneumonia
? Diarrhea
? Malnutrition
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
Y
Wang Xiaochuan Children’s Hospital
patient motherfather
BTK
expression
Wang Xiaochuan Children’s Hospital
Ttcagactgtccttcctctctggactgtaagaatatgtctccagggccagtgtctgctgcgatcgagtcccaccttccaagtcctggcatctcaat
gcatctgggaagctacctgcattaagtcaggactgagcacacaggtgaactccagaaagaagaagctatggccgcagtgattctggagagca
tctttcTgaagcgatcccaacagaaaaagaaaacatcacctctaaacttcaagaagcgcctgtttctcttgaccgtgcacaaactctcctacta
tgagtatgactttgaacgtgggagaagaggcagtaagaagggttcaatagatgttgagaagatcacttgtgttgaaacagtggttcctgaaaaaa
atcctcctccagaaagacagattccgagaagaggtgaagagtccagtgaaatggagcaaatttcaatcattgaaaggttcccttatcccttccag
gttgtatatgatgaagggcctctctacgtcTTCTCCCCaactgaagaactaaggaagcggtggattcaccagctcaaaaacgta
atccggtacaACAGTGATCTggttcagaaatatcacccttgcttctggatcgatgggcagtatctctgctgctctcagacag
ccaaaaatgctatgggctgccaaattttggagaacaggaatggaagcttaaaacctgggagttctcaccggaagacaaaaaagcctcttcccc
caacgcctgaggaggaccagatcttgaaaaagccactaccgcctgagccagcagcagcaccagtctccacaagtgagctgaaaaaggttgt
ggccctttatgattacatgccaatgaatgcaaatgatctaCAGctgcggaagggtgatgaatattttatcttggaggaaagcaacttacca
tggtggagagcacgagataaaaatgggcaggaaggctacattcctagtaactatgtcactgaagcagaagactccatagaaat gtatgagt
Ggtattccaaacacatgactcggagtcaggctgagcaactgctaaagcaagaggggaaagaaggaggtttcattgtcagagactccagc
aaagctggcaaatatacagtgtctgtgtttgctaaatccacaggggaccctcaaggggtgatacgtcattatgttgtgtgttccacacctcagagc
cagtattacctggctgagaagcaccttttcagcaccatccctgagctcattaactaccatcagcacaactctgcaggactcatatccaggctcaaa
tatccagtgtctcaacaaaacaagaatgcaccttccactgcaggcctgggatacggatcatgggaaattgatccaaaggacctgaccttcttgaa
ggagctggggactggacaatttggggtagtgaagtatgggaaatggagaggccagtacgacgtggccatcaagatgatcaaagaaggctcc
atgtctgaagatgaattcattgaagaagccaaagtcatgatgaatctttcccatgagaagctggtgcagttgtatggcgtctgcaccaagcagcg
ccccatcttcatcatcactgagtacatggccaatggctgcctcctgaactacctgagggagatgcgccaccgcttccagactcagcagctgcta
gagatgtgcaaggatgtctgtgaagccatggaatacctggagtcaaagcagttccttcaccgagacctggcagctcgaaactgtttggtaaacg
atcaaggagttgttaaagtatctgatttcggcctgtccaggtatgtcctggatgatgaatacacaagctcagtaggctccaaatttccagtccggtg
gtccccaccggaagtcctgatgtatagcaagttcagcagcaaatctgacatttgggcttttggggttttgatgtgggaaATTTACt
ccctggggaagatgccatatgagagatttactaacagtgagactgctgaacacattgcccaaggcctacgtctctacaggcctcatctggcttca
gagaaggtatataccatcatgtacagttgttggcatgagaaagcagatgagcgtcccactttcaaaattcttctgagcaatattctagatgtcatgg
T
C
T
A
C
Wang Xiaochuan Children’s Hospital
Common variable
immunodeficiency disease(CVID)
? Pathogenesis,unclear
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
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.
Wang Xiaochuan Children’s Hospital
Pre B cell Immature B
cell
IgM (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
Wang Xiaochuan Children’s Hospital
Immunodeficiency
syndromes
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
Ataxia-telangiectasia
? Gene defect,mutation in A-T gene (ATM),
AR
? Clinical manifestations
– Ataxia
– Telangiectasia
– Recurrent infections
– Malignancies
– X-ray sensitivity
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
Wang Xiaochuan Children’s Hospital
Treatment
? General management
? Immunoglobulin
? Replacement therapy
? others
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
Immunoglobulin replacement
? Treatment of severe antibody disorders
? Intramuscular
– 0.1g/kg/m
? Intravenous
– 0.4-0.6g/kg/m
Wang Xiaochuan Children’s Hospital
Immunoglobulin replacement
adverse effects
? Local reactions,intramuscular gammaglobulin,
tenderness,abscesses,fibrosis
? Systemic reaction,Fever,chills,nausea,
vomiting; anaphylactic reaction are unusual
Wang Xiaochuan Children’s Hospital
Specific treatment for cellular
deficiency
? Bone marrow transplantation
? Replacement therapy
– Enzyme replacement
– Gene therapy
– Thymic hormones
– Cytokines
? Fetal thymus transplantation
Wang Xiaochuan Children’s Hospital
Specific treatment of phagocytic
disorders
? Interferon gamma for CGD
? Granulocyte transfusion
Immunodeficiency diseases
Wang,Xiaochuan
Department of Clinical Immunology,
Children’s Hospital of Fudan University
Wang Xiaochuan Children’s Hospital
Pathogens
Environment Material
Immunity
Infectious
Immunity
Allergy
Tumor
Immunity
Autoimmune Disease
PID
Wang Xiaochuan Children’s Hospital
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
? Primary - PID,damage to anatomical barriers
? Secondary - infection,tumor,drug,others
? Physiology- Infants,aged
Wang Xiaochuan Children’s Hospital
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
+ - - - -
Wang Xiaochuan Children’s Hospital
Development of Immunoglobulin
IgG from mother IgG of infant
6Mbirth
100%
IgG level of Infant
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
Schematic diagram of the exposure
of microorganism during early life
fetus Full tern 6M Day care
pathogens
probiotics
Wang Xiaochuan Children’s Hospital
Period of susceptible children
premature
Full term
6M Day care
Wang Xiaochuan Children’s Hospital
Management
? Exclusion of PID
? Clinical features
– Frequency of infection
– Severity
– Complications
? Follow up
Wang Xiaochuan Children’s Hospital
Management
? General medical care (prevention,nutrition、
exercise)
? Complication Treatment
? Medication
– Antibiotics
– Immune regulator
– Immunizations
Wang Xiaochuan Children’s Hospital
(Primary Immunodeficiency
Disease,)
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
50%
20%
10%
18% 2%
Antibody
ComplementPhagocyte
Cell mediated
Combined
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
Classification (old)
? Antibody(B cell) deficiency
? T cell deficiency
? Combined immunodeficiency
? Phagocyte deficiency
? Complement deficiency
Wang Xiaochuan Children’s Hospital
Classification(new)
? Combined Immunodeficiency
? Predominantly antibody deficiency
? Predominantly T-cell deficiency
? Immunodeficiency syndromes
? Phagocyte deficiency
? Complement deficiency
? Others
Wang Xiaochuan Children’s Hospital
Up to 2001 more
then 100 kinds of
reported PID
1,联合免疫缺陷
(1) 无 T有 B
(a)X-连锁 (γ c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
Wang Xiaochuan Children’s Hospital
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.
Wang Xiaochuan Children’s Hospital
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.
Wang Xiaochuan Children’s Hospital
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.
Wang Xiaochuan Children’s Hospital
Characteristics
? Male,onset at 10 months
? Recurrent infection
? Recurrent arthritis
? Deceased serum Igs
? Absence of circulating B cell
Wang Xiaochuan Children’s Hospital
Case continue (Diagnosis)
? Primary Immunodeficiency disease(X-
linked agammaglobulinemia)
? Juvenal Idiopathic Arthritis
? Pneumonia
? Diarrhea
? Malnutrition
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
Y
Wang Xiaochuan Children’s Hospital
patient motherfather
BTK
expression
Wang Xiaochuan Children’s Hospital
Ttcagactgtccttcctctctggactgtaagaatatgtctccagggccagtgtctgctgcgatcgagtcccaccttccaagtcctggcatctcaat
gcatctgggaagctacctgcattaagtcaggactgagcacacaggtgaactccagaaagaagaagctatggccgcagtgattctggagagca
tctttcTgaagcgatcccaacagaaaaagaaaacatcacctctaaacttcaagaagcgcctgtttctcttgaccgtgcacaaactctcctacta
tgagtatgactttgaacgtgggagaagaggcagtaagaagggttcaatagatgttgagaagatcacttgtgttgaaacagtggttcctgaaaaaa
atcctcctccagaaagacagattccgagaagaggtgaagagtccagtgaaatggagcaaatttcaatcattgaaaggttcccttatcccttccag
gttgtatatgatgaagggcctctctacgtcTTCTCCCCaactgaagaactaaggaagcggtggattcaccagctcaaaaacgta
atccggtacaACAGTGATCTggttcagaaatatcacccttgcttctggatcgatgggcagtatctctgctgctctcagacag
ccaaaaatgctatgggctgccaaattttggagaacaggaatggaagcttaaaacctgggagttctcaccggaagacaaaaaagcctcttcccc
caacgcctgaggaggaccagatcttgaaaaagccactaccgcctgagccagcagcagcaccagtctccacaagtgagctgaaaaaggttgt
ggccctttatgattacatgccaatgaatgcaaatgatctaCAGctgcggaagggtgatgaatattttatcttggaggaaagcaacttacca
tggtggagagcacgagataaaaatgggcaggaaggctacattcctagtaactatgtcactgaagcagaagactccatagaaat gtatgagt
Ggtattccaaacacatgactcggagtcaggctgagcaactgctaaagcaagaggggaaagaaggaggtttcattgtcagagactccagc
aaagctggcaaatatacagtgtctgtgtttgctaaatccacaggggaccctcaaggggtgatacgtcattatgttgtgtgttccacacctcagagc
cagtattacctggctgagaagcaccttttcagcaccatccctgagctcattaactaccatcagcacaactctgcaggactcatatccaggctcaaa
tatccagtgtctcaacaaaacaagaatgcaccttccactgcaggcctgggatacggatcatgggaaattgatccaaaggacctgaccttcttgaa
ggagctggggactggacaatttggggtagtgaagtatgggaaatggagaggccagtacgacgtggccatcaagatgatcaaagaaggctcc
atgtctgaagatgaattcattgaagaagccaaagtcatgatgaatctttcccatgagaagctggtgcagttgtatggcgtctgcaccaagcagcg
ccccatcttcatcatcactgagtacatggccaatggctgcctcctgaactacctgagggagatgcgccaccgcttccagactcagcagctgcta
gagatgtgcaaggatgtctgtgaagccatggaatacctggagtcaaagcagttccttcaccgagacctggcagctcgaaactgtttggtaaacg
atcaaggagttgttaaagtatctgatttcggcctgtccaggtatgtcctggatgatgaatacacaagctcagtaggctccaaatttccagtccggtg
gtccccaccggaagtcctgatgtatagcaagttcagcagcaaatctgacatttgggcttttggggttttgatgtgggaaATTTACt
ccctggggaagatgccatatgagagatttactaacagtgagactgctgaacacattgcccaaggcctacgtctctacaggcctcatctggcttca
gagaaggtatataccatcatgtacagttgttggcatgagaaagcagatgagcgtcccactttcaaaattcttctgagcaatattctagatgtcatgg
T
C
T
A
C
Wang Xiaochuan Children’s Hospital
Common variable
immunodeficiency disease(CVID)
? Pathogenesis,unclear
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
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.
Wang Xiaochuan Children’s Hospital
Pre B cell Immature B
cell
IgM (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
Wang Xiaochuan Children’s Hospital
Immunodeficiency
syndromes
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
Ataxia-telangiectasia
? Gene defect,mutation in A-T gene (ATM),
AR
? Clinical manifestations
– Ataxia
– Telangiectasia
– Recurrent infections
– Malignancies
– X-ray sensitivity
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
Wang Xiaochuan Children’s Hospital
Treatment
? General management
? Immunoglobulin
? Replacement therapy
? others
Wang Xiaochuan Children’s Hospital
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
Wang Xiaochuan Children’s Hospital
Immunoglobulin replacement
? Treatment of severe antibody disorders
? Intramuscular
– 0.1g/kg/m
? Intravenous
– 0.4-0.6g/kg/m
Wang Xiaochuan Children’s Hospital
Immunoglobulin replacement
adverse effects
? Local reactions,intramuscular gammaglobulin,
tenderness,abscesses,fibrosis
? Systemic reaction,Fever,chills,nausea,
vomiting; anaphylactic reaction are unusual
Wang Xiaochuan Children’s Hospital
Specific treatment for cellular
deficiency
? Bone marrow transplantation
? Replacement therapy
– Enzyme replacement
– Gene therapy
– Thymic hormones
– Cytokines
? Fetal thymus transplantation
Wang Xiaochuan Children’s Hospital
Specific treatment of phagocytic
disorders
? Interferon gamma for CGD
? Granulocyte transfusion
