Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Immunodeficiency Diseases

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Part 1. Introduction

Part 2. Primary immunodeficiency diseases

Part 3. Secondary immunodeficiency diseases

Part 4. Diagnosis and treatment of immunodeficiency

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Immunodeficiency disease, IDD: results from a

genetic or developmental defect or acquired

factors in the immune system, and is a syndrome

mostly characterized by infection in clinic.

Part 1. Introduction

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Pathogenesis: abnormalities of immunocyte 、 molecules in development 、 differentiation 、 metabolism 、 regulation, etc.

Clinical features: increased susceptibility to infection 、 the

infection of low virulence pathogens.

increased incidence of malignant tumor 、 autoimmune disease 、 hypersensitivity.

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Immunodeficiency disease can be divided into

two types:

primary immunodeficiency disease, PIDD

— results from a genetic factors.

secondary immunodeficiency disease, SIDD

— results from acquired factors .

Classification of Immunodeficiency disease

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Inducement: heredity 、 developmental defect.

Age: infancy and childhood.

Pathogenesis: the differentiation and development

of hemopoietic stem cells.

Part 2 Primary immunodeficiency diseases (PIDD)

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

1 、 PIDD characterized by humoral immunity deficiency.

2 、 PIDD characterized by cellular immunity deficiency.

3 、 Combined immunodeficiency diseases .

4 、 Nonspecific immunodeficiency diseases.

PIDD can be divided into:

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

造血干细胞

淋巴干细胞 髓样干细胞

前 B 细胞 前 T 细胞单核细胞中性粒细胞

B 淋巴细胞 T 淋巴细胞

记忆 B 细胞浆细胞

网状细胞发育不全

SCID

DiGeorge综合症胸 腺

WA 综合症

SCID

选择性免疫球蛋白缺乏症症

性联高 IgM 综合症

XLA

白细胞粘附无能

先天无粒细胞血症

慢性肉芽肿

免疫细胞分化途径与免疫缺损

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Congenital defects that

interrupt hematopoiesis

or impair functioning of

immune-system cells

result in various

immunodeficiency

diseases.

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

1.PIDD characterized by humoral immunity deficiency

Features ： increased susceptibility to bacteria 、 enterovirus 、 intestine parasites,

delayed in growth and development ， increased incidence of autoimmune

disease, absent or reduced levels of Ig.

Primary antibody deficiency mainly results from abnormal development of the B cell system.

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Pathogenesis: the block of the differentiation and

development of B cells, reduced

function of Th cells.

1 ） Bruton’s syndrome （ x-linked agammaglobulinaemia ） 2 ） Selectively IgA deficiency

3 ） Ig immunodeficiency with increased IgM .

（ hyper-IgM syndrome ， HIGM）

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

The first immunodeficiency disease to be understood in detail, the underlying deficiency being discovered in 1952.

Affects males have few or no B-cells in their blood or lymphoid tissue, their lymph nodes are very small and their tonsils are absent.

Their serum usually contains no IgA,IgM,IgD,IgE, and only small amounts of IgG.

1 ） Bruton’s syndrome （ x-linked agammaglobulinaemia XLA

）

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

1 ） Bruton’s syndrome （ x-linked agammaglobulinaemia XLA

）Immunological features: the absence of B cells in

blood and IgG.

Pathogenesis: block in the differentiation and

development of the pre-B cells.

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

1 2

albumin globulin

（ a ）

（ b ）

（ c ）

Bruton’s syndrome （ x-linked agammaglobulinaemia XLA ）

Electrophoresis Analysis of Serum Protein

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Genetic features: x-linked recessive inheritance, male.

Clinical features: recurrent bacterial infections ， no

Ab

responds to vaccination.

Treatment: inject pooled gamma globulin preparations.

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Immunological features: lack serum IgA, <50mg/L ， decreased level of sIgA.

Pathogenesis: failure in terminal differentiation of

B cells.

2 ） Selectively IgA deficiency: the most common immunodeficiency

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Clinical features: recurrent infections in respiratory tract 、 alimentary canal 、 urogenital tract.

Treatment: breast feeding ， few of them can automatically

resume the ability to produce IgA.

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Immunological features ： increased level of IgM ，decreased levels of other Ig.

Pathogenesis: absent of the T cell effector CD40L ，CD40L can not bind to CD40 of B cells ， and

therefore do not stimulate B cells to undergo Ab

class switching.

3 ） Hyper-IgM syndrome ， HIGM

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Genetic features ： x-linked recessive

inheritance ， boy.

Clinical features ： recurrent pyogenic infections ， increased level of IgM ， decreased levels of IgA 、 IgG.

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Deficiencies caused only by the loss of cellular

immunity are very rare, as most T cell deficiencies

result in severely compromised humoral immunity

as well.

T cell defects occurring during development.

2.PIDD characterized by cellular immunity deficiency

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Patient with no T cells, or poor T cell function, are

susceptible to opportunistic infections.

Because B-cell function in human is largely T-cell

dependent, T-cell deficiency also result in humoral

immunodeficiency.

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

T-cell deficiency leads to a combined deficiency of

both humoral and cell-mediated immunity.

Features ： increased susceptibility to intracellular

microbes 、 death in the early age.

tumor. no reaction to DTH, no reaction

to HVGR (host versus graft reaction)..

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

1 ） DiGeorge syndrome (genetical thymus hypoplasia ，

third and fourth pharyngeal arch syndrome.

2 ） Structure and function defect of T cell surface

molecules.

Cellular immunity deficiency

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Immunological features ： absent or hypogenesis of the thymus.

Genetic features ： decreased function of

the cellular immunity ， defect function of the

parathyroid gland.

1 ） DiGeorge syndrome

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

DiGeorge syndrome

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Clinical features: recurrent infections of

intracellular bacteria ， no reaction to HVGR （ host

versus graft reaction,HVGR ） .

Treatment ： fetal thymic transplantation

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

1. absent of the TCR ： TCR

2. mutant of the CD3 molecular ：

reduced ability of the immune response.

2 ） Structure and function defect of T cell surface molecules

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

There is lymphocyte deficiency and thymus does not develop.

SCID results in severe recurrent infections and is usually fatal in the early years of life.

They have prolonged diarrhea due to rotavirus or bacterial infection of the gastrointestinal tract and develop pneumonia.

3. Combined immunodeficiency diseases

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

lose of the humoral immunity and cellular immunity at the same time.

1)X-linked severe combined immunodeficiency disease.

(X-linked SCID ， XSCID).

2)immunodeficiency diseases with enzymes defect.

adenosine deaminase ， ADA.

purine nucleoside phosphorylase ， PNP.

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

1 ） X-linked severe combined immunodeficiency disease. (X-linked SCID ， XSCID)

Pathogenesis ： gene mutation of IL-2 receptor chain reduced

numbers of peripheral blood T cells and NK cells.

Treatment ： bone marrow transplantation.

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

（ 1 ）症状和体征：IL-2R IL-4R IL-7R IL-9R IL-15R

Relationship between IL-2R chain and cytokine receptor

commonchain

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Severe Combined Immunodeficiency ， SCID(Bubble boy)

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Pathogenesis ： gene mutation of adenosine

deaminase ， ADA and purine

nucleoside phosphorylase， PNP.

Treatment ： bone marrow transplantation.

2)Immunodeficiency diseases with enzymes defect.

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

GMPAMP IMP

guanosine ADA

hypoxanthine

PNP

guanine

PNP

xanthine

Uric acid

adenosine deoxyadenosine

guanosine deoxyguanosine

dAMP

dADP

dATP

dGMP

dGDP

dGTP inhibition ribonucleotide reductase

T 、 B proliferation↓

adenosine inosine

Relationship between gene mutation of ADA / PNP and Immunodeficiencydiseases

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

5 %5 %

50 %

20 %20 %

Autosomal recessive SCID

X-linked SCID

ADA defect

PNP defect

other

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

4 、 Nonspecific immunodeficiency diseases

1 ） deficiency of phagocytes

Immunological features ： decreased number and

defected function of

macrophages.

Clinical features ： chronic granulomatous disease.

Pathogenesis: deficient in NADH/NADPH oxidase,

decreased the ability in bacterial

killing dependent on oxygen radical .

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

NADH ( nicotinamide adenine dinucleotide-reduced)

NADPH ( reduced form of nicotinamide-adenine dinucleotid)

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

chronic granulomatous disease （ CGD ）

cytochromeB

bacteria

flavoprotein

phagosome

bacteria

phagosome

macrophages

NADPH H+NADPH H+

e- +O2

O2-

H+

H2O2

Normal

macrophages

Anergy

macrophages

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

A prolonged DTH response can lead to formation of a granuloma, a nodule-like mass. Lytic enzymes released from activated macrophages in a granuloma can cause extensive tissue damage.

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

genetic deficiencies of complement components

or complement regulatory proteins.

hereditary angioneurotic oedema: deficiency of

C1INH (C1 esterase inhibitor) ， vasodilatation ，increased permeability of the blood capillary skin 、mucous membrane edema.

2 ） Deficiency of complement components

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Factors caused acquired immunodeficiency:

Secondary or acquired immunodeficiency is the most common immunodeficiency, mainlyaffecting phagocytic and lymphocyte function.

It may result from infection (HIV), malnutrition, aging, cytotoxic therapy.

Part 3 、 Secondary immunodeficiency diseases

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Table : Factors Caused Secondary Immunodeficiency

Factor Components affectedMalnutrition

Tumor

Cytotoxic drugs/irradiation

AgingTrauma

Would wide the major predisposing

TGF ( Transforming growth factors): a group cytokines identified by their ability to promote fibroblast growth, that are generally Immunosuppressive.Widely used for tumor therapy, but also kills cells.

important to immune responses.

Increased infections.Increased infections related to release of immunosuppressive molecular.

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

1 、 succeed some diseases SIDD .

2 、 iatrogenic SIDD .

3 、 acquired immunodeficiency syndrome,

AIDS.

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Infection: virus infection decreased function of

cellular immunity, decreased function of the T

cells.

malignant tumors: decreased function of cellular

immunity, decreased function of the T cells,

notable decreased function of the T and B cells.

1 、 Succeed some diseases SIDD

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Loss of proteins ： excessive consume or insufficient

synthesis : decreased level of Ig, decreased function

of humoral immunity.

severe malnutrition: decreased function of the T cells.

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

1)using immunosuppressive drugs 、 some antibiotics,

antineoplastic for a long time.

2)damage by irradiation.

2 、 Iatrogenic SIDD

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Glucocorticoids are the most powerful naturally occurring modulators of the immune response and have profound effects at most levels and on most components.

In addition to their direct hormonal action on immune cell traffic and function, steroids have a substantial influence on cytokine synthesis, thereby also exerting a powerful indirect effect.

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Human immunodeficiency virus (HIV) causes AIDS and is transmitted sexually, in blood or blood products, and perinatally.

●Two main variants: HIV-1 and HIV-2

●WHO report: total infected will reach 40 million by 2004.

3 、 Acquired immnodeficiency syndrome ， AIDS

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

The global AIDS epidemic. The estimated worldwide distribution of AIDS cases as of December 2000.

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

HIV and AIDS

Patients with AIDS present with opportunistic infections caused by certain bacteria, viruses, fungi, and protozoa

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

This is due to greatly reduced helper T cell numbers by infection with the retrovirus human immunodeficiency virus (HIV).

This virus specifically infects and kills cells bearing the CD4 protein as a surface receptor.

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

1)   etiology ： RNA retrovirus

HIV__is a single stranded diploid RNA virus 100-120nm in diameter

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Structure of HIV

nucleocapsid

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

membrane: derived from the host cell membrane, two kinds

of glycoproteins: gp120 and gp41.

gp41 is a transmembrane protein, and gp120 is an external

protein.

HIV: CD4 antigen is the receptor for the virus

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

HIV - life cycle

enter into cellCD4+T cell is the major target cell

human HeLa cells

human HeLa cells transfected with CD4 antigen

without infection infection

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

HIV gp120 infect CD4 host cells lead to

（ 1 ） virus replication ， cell death.

（ 2 ）  fusion of the cells multinucleated giant cells ， cell death.

（ 3 ） decrease or invert the ratio of CD4/CD8.

2 ） Pathogenesis and Immunological features

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Latent period ： 6 month—4 year

Infection phase ： influenza-like symptom 、 infectious

Abs production ： 3-20 weeks

Symptom ： AIDS related complex ARC

（ 1 ）   opportunistic infections

（ 2 ）  malignant tumors ： Kaposi’s sarcoma 、 malignant lymphoma

（ 3 ）   abnormal of the central nervous system

3 ） Clinical features

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

major group at risk ： homosexual,drug abusers,

infected blood or blood products.

spread manner ： sexual contact,blood,

mother-to-child transmission.

4 ） epidemiology

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

5 ） detection and Treatment

Ab detection ：Ag detection ：P24--acute infective stage and advanced stage

Treatment ： vaccine

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Family history

Evaluation of specific immune components

Antibiotics and antibodies

Bone marrow transplants and gene therapy

Part 4. Diagnosis and treatment of immunodeficiency

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

1.Family history

Since defective genes can be inherited, an

investigation into the family history is especially

important in the diagnosis of primary immuno-

deficiency

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Very important for determining appropriate treatment

By assay of: Ig classes and B cell numbers T cell subset numbers and their cytokine production

2. Evaluation of specific immune components

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Antibiotics therapy for infections.

Antibodies from a pool of donors are used for antibody deficiencies.

3. Antibiotics and antibodies

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Treatment for these defects may eventually involve

replacing faulty genes, once identified, in the patient’s

stem cells with a normal gene.

4. Bone marrow transplants and gene therapy

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

To mast the concept and the features of the immunodeficiency diseases.

To be familiar with the immunological features of PIDD.

To know the classification of the immunodeficiency diseases and

the features of all types of immunodeficiency diseases.

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

More info:http://immunology.xjtu.edu.cn/lesson2005/mianyiquexian/INDEX.HTM

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University

Serologic profile of HIV infection showing three stages in the

infection process. Soon after infection, viral RNA is detectable

in the serum. However, HIV infection is most commonly

detected by the presence of anti-HIV antibodies after

seroconversion, which normally occurs within a few months

after infection. Clinical symptoms indicative of AIDS generally

do not appear for at least 8 years after infection, but interval

is variable. The onset of clinical AIDS is usually signaled by

a decrease in T-cell numbers and an increase in viral load.

Department of Pathogenic Microbiology and Immunology, Medical School of Xi’an Jiaotong University