Transcript Congenital immunodeficiencies caused by defects in innate

Congenital and acquire
Immunodeficiency
Wei Chen, Associate professor
Institute of Immunology
E-mail:[email protected]
http://mypage.zju.edu.cn/566 8888
Objectives
To understand the concept of
immunodeficiency.
To know the main types of primary
immunodeficiency diseases.
Be able to describe characteristics and
consequence of HIV infection.
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency diseases
Immunodeficiency
Defects in the development and functions
of the immune system.
Result in increased susceptibility to
infections and in an increased incidence of
certain cancers.
Disorders caused by defective immunity are
called immunodeficiency diseases.
General feature of
immunodeficiency diseases
The principal consequence of immunodeficiency is an
increased susceptibility to infection.
Patients with immunodeficiencies are also susceptible to
certain types of cancer.
Paradoxically, certain immunodeficiencies are associated
with an increased incidence of autoimmunity.
Immunodeficiency may result from defects in
lymphocyte development or activation or from defects in
the effector mechanisms of innate and adaptive
immunity.
Classification
Primary or congenital immunodeficiencies
Present at birth
Result from genetic abnormalities in one or more
components of the immune system
Secondary or acquired immunodeficiencies
Later in life
Result from infections, malnutrition, or treatments that
cause loss or inadequate function of various components
of the immune system
Most common is acquired immunodeficiency syndrome,
or AIDS
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency diseases
Primary immunodeficiency
diseases
Severe Combined Immunodeficiencies (SCID)
Antibody Deficiencies: Defects in B Cell
Development and Activation
Defects in T Lymphocyte Activation and Function
Defects in Innate Immunity
Multisystem Disorders with immunodeficiency
Features of immunodeficiency diseases
congenital immunodeficiencies caused by
defects in lymphocyte maturation
Severe Combined Immunodeficiency
Syndromes (SCID)
Congenital immunodeficiencies that affect both humoral
and cell-mediated immunity are called combined
immunodeficiencies.
characterized by deficiencies of both B and T cells or
only of T cells; in the latter cases, the defect in humoral
immunity is due to the absence of T cell help.
Children with SCID usually have infections during the
first year of life.
Severe Combined Immunodeficiency
Syndromes (SCID)
Athymic - DiGeorge Syndrome
X-linked SCID (c deficiency)
Adenosine deaminase deficiency (腺苷脱氨酶)
Jak3 kinase deficiency
Purine nucleoside phosphorylase deficiency
Bare lymphocyte syndrome
RAG1 and RAG2 deficiency
Precursor T cell differentiation defect
Athymic - DiGeorge Syndrome
Sporadic microdeletion of 22q, TBX1 gene (T-box1)
Lack of T helper (Th) cells , Cytotoxic T cells (CTL) and T
regulatory (Treg) cells
B cells are present but T-dependent B cell responses are
defective
Anti-viral and anti-fungal immunity impaired
Developmental defect in the 3rd and 4th pharyngeal
pouch
Results in facial defect and congenital heart disease
DiGeorge syndrome
X-Linked SCID: Common Cytokine Receptor
Gamma Chain (c) Deficiency
Most common form of SCID (40%)
Responsible gene: γc– the common subunit of
receptors for IL-2, IL-4, IL-7, IL-9, and IL-15
Very low T cells and NK cells with low to normal
numbers of B cells
Nude Athymic mouse
FOXN1 gene knock-out (autosomal recessive)
Hairless
Should be maintained in pathogen-free environment
T helper cell defect
Results in impaired cytotoxic T cell activity and Th-
dependent B cell responses due to Th cell defect
Accept xenografts
Antibody Deficiencies: Defects in B
Cell Development and Activation
Bruton’s (X-linked) Agammaglobulinemia
Common Variable Immunodeficiency (CVID)
Autosomal Recessive Hyper-IgM Syndrome
B Cell Receptor Deficiencies
Selective IgA Deficiency
IgG Subclass Deficiency
XLA - BTK defect
Defect in B cell
maturation
Genetic disorder - gene
on X-chromosome
codes for Bruton’s
tyrosine kinase - BTK
essential for B cell
development
Essential role of BTK
Bruton’s X-linked Agammaglobulinemia
The absence of B cells in blood and IgG
x-linked recessive inheritance, males
Child clinically well for first 6 months of life
Recurrent upper/lower respiratory tract infections with
encapsulated bacteria
Sepsis (败血症), meningitis (脑膜炎), skin infections
Paucity of lymphoid tissue (tonsils, adenoids)
Treatment: inject pooled gamma globulin preparations
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症),
usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronic/recurrent respiratory infections, diarrhea(腹泻)
Tendency to develop autoimmunity and lymphoid
malignancies
Linkage to HLA Class III Region in 2/3 of patients
One gene identified: ICOS (B7h) (activation antigen on T
cells)
Defects in Innate Immunity
Phagocyte Deficiencies:
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes: the ChédiakHigashi syndrome
Inherited defects in TLR Pathways, NF-κB signaling
and type I Interferons
IL-12/IFN pathway deficiencies
Congenital immunodeficiencies caused by
defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen
peroxide due to mutations in one of four
proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive
organisms, esp. Staph aureus, Serratia
marcescens, mycobacteria, and fungi such as
Aspergillus
Chronic granulomatous disease
Note cervical nodal
abscess(头颈淋巴结脓肿)
Gingivitis and periodontitis
(牙龈炎和牙周炎)
Abscess indenting the
oesophagus(食道脓肿)
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual, promiscuous heterosexual, i.v.
drug users, transfusion, infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii (卡氏肺囊虫),
Candida albicans, Mycobacterium avium, etc.
Patients with HIV have high incidence of cancers such as Kaposi
sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse
transcriptase)
Copy (provirus) inserted into the host
genome
When it is expressed to form new virions,
the cell lyses
Alternately, it may remain latent in the cell
for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells: gp120 binds to CD4 and CXCR4 on
T cells or CCR5 on DC and M.
Production of viral DNA and its integration into the
host genome.
Expression of viral genes: production of viral RNAs
and then proteins to form a core structure.
Production of viral particles: the core structure
migrates to the cell membrane, acquires a lipid
envelope from the host, and the viral particle is shed.
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and
may be reactivated to produce infectious virus. This
viral production leads to death of infected cells and
uninfected lymphocytes, subsequent
immunodeficiencies and clinical AIDS.
The depletion of CD4+ T cells after HIV infection is due
to a cytopathic effect of the virus, resulting from
production of viral particles, as well as death of
uninfected cells.
Course of AIDS
Dissemination of virus;
Seeding of lymphoid organs
Anti-HIV Ab/CTL
ACUTE
PHASE
CHRONIC
PHASE AIDS
AIDS
(<200cells/mm3)
The pathogenesis
of AIDS
The earliest innate and adaptive immune
responses detected after HIV transmission
Nat Rev Immunol. 2010,10:11
Animal Models
Primate Model:
HIV grows in chimpanzees but do not develop AIDS
Simian immunodeficiency virus (SIVagm in African
green monkey – no disease; SIVmac in Macaques –
AIDS like);
Mouse Model:
Grows in Severe Combined Immunodeficiency (SCID)
mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be
blocked
Attachment/entry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)
Nucleoside analog - is incorporated into
growing chain and causes termination
Side effects
Resistant mutants develop
Nevirapine
Inhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough!
Responsible for rapid drop in number of
deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing
resistance
Can reduce virus to undetectable levels
Expensive ($15,000/yr)
Therapies
Ongoing work to develop drugs to interfere
with integration and with attachment/entry
Takes many years to pass tests for safety and
efficacy
Vaccines
Has been much harder to develop a vaccine
for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies, but they don’t protect