G.2014-immuno~ (15.immunodeficiency diseases-xm)

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

Part 1. Introduction
Part 2. Primary immunodeficiency diseases
Part 3. Secondary immunodeficiency diseases
Part 4. Diagnosis and treatment of immunodeficiency

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

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.

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

Inducement: heredity 、 developmental defect.
Age: infancy and childhood.
Pathogenesis: the differentiation and development
of hemopoietic stem cells.
Part 2 Primary immunodeficiency diseases (PIDD)

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:

造血干胞细
淋巴干胞细髓干胞样细
前 B 胞细前 T 胞细
核胞单细中性粒胞细
B 淋巴胞细
T 淋巴胞细
记忆 B 胞细胞浆细
网状胞育不全细发网状胞育不全细发
SCIDSCID
DiGeorge
合症综
DiGeorge
合症综
胸腺
WA 合症综WA 合症综
SCIDSCID
性免疫球选择
蛋白缺乏症症
性免疫球选择
蛋白缺乏症症
性高联 IgM 合症综性高联 IgM 合症综
XLAXLA
白胞粘附无能细白胞粘附无能细
先天无粒
胞血症细
先天无粒
胞血症细
慢性肉芽肿慢性肉芽肿
免疫胞分化途细
径与免疫缺损

Congenital defects that
interrupt hematopoiesis
or impair functioning of
immune-system cells
result in various
immunodeficiency
diseases.

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.

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 ）

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
）

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.

α1 α2
β γ
albumin globulin
（ a ）
（ b ）
（ c ）
Bruton’s syndrome （ x-linked agammaglobulinaemia XLA ）
Electrophoresis Analysis of Serum Protein

Genetic features: x-linked recessive inheritance, male.
Clinical features: recurrent bacterial infections ， no
Ab
responds to vaccination.
Treatment: inject pooled gamma globulin preparations.

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

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.

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

Genetic features ： x-linked recessive
inheritance ， boy.
Clinical features ： recurrent pyogenic infections ，
increased level of IgM ，
decreased levels of IgA 、 IgG.

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

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.

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)..

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

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

DiGeorge syndrome

Clinical features: recurrent infections of
intracellular bacteria ， no
reaction to HVGR （ host
versus graft reaction,HVGR ） .
Treatment ： fetal thymic transplantation

1. absent of the TCR ： TCRαβ
2. mutant of the CD3 molecular ：
reduced ability of the immune response.
2 ） Structure and function defect of T cell surface
molecules

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

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.

1 ） X-linked severe combined immunodeficiency disease.
(X-linked SCID ， XSCID)
Pathogenesis ： gene mutation of IL-2 receptor γ chain reduced
numbers of peripheral blood T cells and NK
cells.
Treatment ： bone marrow transplantation.

（ 1 ）症状和体征：
IL-2R IL-4R IL-7R IL-9R IL-15R
Relationship between IL-2R γ chain and cytokine receptor
common γ chain

Severe Combined Immunodeficiency ， SCID(Bubble
boy)

Pathogenesis ： gene mutation of adenosine
deaminase ， ADA and purine
nucleoside phosphorylase ，
PNP.
Treatment ： bone marrow transplantation.
2)Immunodeficiency diseases with enzymes defect.

GMPAMP IMP
guanosine
ADA
hypoxanthine
PNP
guanine
PNP
xanthine
Uric
acid
adenosine
deoxyadenosine
guanosine
deoxyguanosine
dAMP
dADP
dATP
dGMP
dGDP
dGTPinhibition ribonucleotide
reductase
inhibition ribonucleotide
reductase
T 、 B proliferation↓T 、 B proliferation↓
adenosine inosine
Relationship between
gene mutation of
ADA / PNP and
Immunodeficiency
diseases

5 %
5 %
50 %
20 %
20 %
Autosomal
recessive
SCID
X-linked SCID
ADA
defect
PNP defect
other

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

NADH ( nicotinamide adenine dinucleotide-reduced)
NADPH ( reduced form of nicotinamide-adenine
dinucleotid)

chronic granulomatous disease （ CGD ）
cytochromeB
bacteria
flavoprotein
phagosome
bacteria
phagosome
macrophages
NADPH H+
NADPH H+
e-
+O2
O2
-
H+
H2O2
Normal
macrophages
Anergy
macrophages

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.

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

Factors caused acquired immunodeficiency:
Secondary or acquired immunodeficiency is
the most common immunodeficiency, mainly
affecting phagocytic and lymphocyte function.
It may result from infection (HIV), malnutrition,
aging, cytotoxic therapy.
Part 3 、 Secondary immunodeficiency diseases

Table : Factors Caused Secondary Immunodeficiency
Factor Components affected
Malnutrition
Tumor
Cytotoxic
drugs/irradiation
Aging
Trauma
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.

1 、 succeed some diseases SIDD .
2 、 iatrogenic SIDD .
3 、 acquired immunodeficiency syndrome,
AIDS.

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

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.

1)using immunosuppressive drugs 、 some antibiotics,
antineoplastic for a long time.
2)damage by irradiation.
2 、 Iatrogenic SIDD

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.

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

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

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

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.

1) etiology ： RNA retrovirus
HIV__is a single stranded diploid RNA virus 100-
120nm in diameter

Structure of HIV
nucleocapsid

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

HIV - life cycle
enter into cell
CD4+
T cell is the major target cell
human HeLa
cells
human HeLa cells
transfected with
CD4 antigen
without infection infection

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

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

major group at risk ： homosexual,drug abusers,
infected blood or blood products.
spread manner ： sexual contact,blood,
mother-to-child transmission.
4 ） epidemiology

5 ） detection and Treatment
Ab detection ：
Ag detection ：
P24--acute infective stage and advanced stage
Treatment ： vaccine

Family history
Evaluation of specific immune components
Antibiotics and antibodies
Bone marrow transplants and gene therapy
Part 4. Diagnosis and treatment of immunodeficiency

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

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

Antibiotics therapy for infections.
Antibodies from a pool of donors are used for
antibody deficiencies.
3. Antibiotics and antibodies

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

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.

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

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.

G.2014-immuno~ (15.immunodeficiency diseases-xm)

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G.2014-immuno~ (15.immunodeficiency diseases-xm)