Download Immunodeficiency

IMMUNODEFICIENCIES
Dr. Gülderen Yanıkkaya Demirel
What is Immunodeficiency?
 A failing of one or more of the body’s defensive
mechanisms resulting in morbidity or mortality.
 Any part of the immune system can be deficient cells,
proteins, signalling mechanisms…….
 The body is susceptible to infection by organisms that
meet with little or no resistance.
 Or, in certain cases, other homeostatic systems in the
body will be disrupted by the defect.
 Severity is variable.
 May be Primary or Secondary.
IMMUNODEFICIENCIES
 Primary (inherited)
 Secondary (to some other)
 Physiological
Immunodeficiency
(Defect in one or more components of immune system)
Types:
 Primary: Mutation in genes controlling immune
system
(e.g. Recurrent, severe infection in children)
 Secondary: Acquired as a consequence of other
diseases or environmental factors
(e.g. infection, malignancy, aging, starvation,
medication, drugs)
Clinical features associated with
immunodeficiency
Feature frequency present and highly
suspicious:
 Chronic infection
 Recurrent infection (more than expected)
 Unusual microbial agents
 Incomplete clearing of infection
 Incomplete response to treatment
Clinical features associated with
immunodeficiency

Feature moderately suspicious
Diarrhea (chronic)
Growth failure
Recurrent abscesses
Recurrent osteomyelitis

Feature associated with specific
immunodeficiency disorder
Telangiectasia
Partial albinism
CLASSIFICATION of PRIMARY
IMMUNDEFICIENCIES
 Combined T cell and B cell immunodeficiencies
 Predominantly antibody deficiencies
 Other well defined immunodeficiency
syndromes
 Diseases of immune dysregulation
 Congenital defects of phagocyte number,
function or both
 Defects in innate immunity
 Autoinflammatory disorders
 Complement deficiencies
Primary Immunodeficiencies
Stem Cell
Reticular Dysgenesis
Lymphoid
Progenitor
Severe combined
Immunodeficiency
SCID
Pre-T
Myeloid
Progenitor
Congenital
Agranulocytosis
Neutrophil
Chronic
Granulomatous
Disease (x or D)
Monocyte
Leukocyte
Adhesion
Deficiency
Pre-B
x-linked
agglobulinemia
xLA
Plasma
Cell
Common Variable Hypogglobulinemia
/ x-linked hyperIgM syndrome/Selective Ig
deficiency
Mature B
Memory B
WAS=WiskottAldrich Syndrome x
DiGeorge
Syndrome D
Thymus
Mature
T
WAS
Bare Lymphocyte
Syndrome
Phagocyte Deficiencies:
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Chediak- Higashi syndrome
IL-12 / IFNg pathway deficiencies
Chronic or cyclic neutropenia
Leucocyte Adhesion Defect (LAD)
Defects in T cell-B cell interactions
Btk=Bruton tyrosine kinase
Defect (XLA)
IL-2Rg defect
IL-2Rg
IL-2, 4, 7, 9, 15
CD40L XHM
JAK3
defect
JAK-3
TCR
CD4
RAG
B
1/2
MHC II
Bare Lymphocyte
Syndrome (MHC II- ve)
RAG=Recombinase activating gene defect (SCID)
JAK=Janus kinase
Btk
Ag
Ag
RAG
J
1/2
T cell
CD40
Ig
B cell
Adaptive Immunity Deficiency
 T cell deficiency

Susceptible to intracellular bacterial infection
 Susceptible to viral, parasitic and fungal infection
 B cell deficiency
 Susceptible to extracellular bacterial infection
 Severe Combined Immunodeficiency Disease (SCID)
 T and B cell functions defective
 Usually fatal
 Transplacental/milk transmission of Abs
 TCR gene rearrangement lacking
 Myeloid and erythroid components intact
Ig Levels vs Age
Overview of B-Cell
Development
Bone Marrow
Periphery
Y
IgM
Y
IgM
IgD
Y
Y
Antigen
Y Y
Y Y
IgM
Plasma Cell
Lymphoid
Stem Cell
ProB Cell
PreB Cell
Immature Mature
B Cell
B Cell
Y
Activated
B Cell
Memory
B Cell
Antigen Independent
Primary Lymphoid Organ
Antigen Dependent
Secondary Lymphoid Organs
Y
Hyper IgM syndrome
Serum levels of immunoglobulin in
Hyper IgM syndrome
IgG↓
IgA↓
IgE↓
IgM ↑↑
Hyper IgM syndrome
 Defect in CD40 ligand
CD40
ligand
T cell
CD40
B cell
Ig Class
switch
Selective IgA Deficiency
Selective IgA deficiency is the most common
ID disorder.
The
prevalence is about 1:700.
Pathogenesis : block in B cell differentiation
is due to intrinsic B cell defect or abnormal T
cell help such as production of cytokine
(TGF-B,IL-5) or in B cell responses to these
cytokines.
IgA Deficiency
 Clinical feature: Recurrent sinopulmonary
infection, gastrointestinal disorders, allergy,
cancer and autoimmune disease.
 IgA Deficiency and genetic factors: association
with HLA-A2, B8 and DW3 or A1 and B8.
 IgA Deficiency and drug.
 Serum IgA<5mg/dl but normal IgM and IgG
 Immunopathogenesis :arrest in the B cell
differentiation.
Selective IgG subclass deficiency
 Total serum IgG levels are normal
 One or more subclasses are below normal.
 IgG3 deficiency is the most common subclass in
adults.
 IgG2 deficiency associated with IgA deficiency in
children.
 Pathogenesis: abnormal B cell differentiation.
 Some individual have recurrent bacterial
infection.
Nude Athymic mouse
Secondary or Acquired
Immunodeficiencies
 Agent-induced immunodeficiency: e.g.
infections, metaboic disturbance, trauma,
corticosteroids, cyclosporin A, radiation,
chemotherapy
 Acquired Hypogammaglobulinemia (Low levels
of Ig; recurrent infections; treat with Ig)
Secondary Immunodeficiency
- Infection
- Renal failure, or protein losing enteropathy
- Leukaemia or Lymphoma
- Myeloma
- Extremes of age
- Certain Drug Therapies
MALNUTRITION
• Most common cause of secondary immune
deficiency.
• Protein-calori malnutrition can lead to
abnormalities of T cells, B cells and phagocytes
• Atrophic and fibrotic thymus
• Reduced lymphocyte proliferation in response to
antigens.
INITIAL SCREENING for ID’s
 Blood Count
 Quantitative Immunoglobulins
 Antibody responses to previous vaccines
 Isoagglutinin (Anti-A and Anti-B) titers
 Total hemolytic complement
 Infection Evaluation (ESR, appropriate
cultures, X-rays)
Human Immunodeficiency Virus
 Discovered in 1983
 Luc Montagnier and Robert Gallo
 Retrovirus
 HIV-1 and HIV-2
 Patients with low CD4+ T cells
 Homosexual; promiscuous heterosexual, i.v. drug users;
transfusion; infants born to infected mothers
 Opportunistic infections with Pnuemocystis carinii, Candida
albicans, Mycobacterium avium, etc.
 Kaposi sarcoma
Kaposi Sarcoma
Acquired Immunodeficiency Syndrome (AIDS)
Structure of HIV-1
gp120
gp41
Envelope
env
Protease
Reverse
Trascriptase
Integrase
pol
Matrix (p17)
gag
Genome
Capsid (p24)
HIV Infection
Coreceptors: Chemokine receptors
T cell-tropic (Syncitium-inducing)
gp120
CXCR4:
SDF1 (Stromal cell
derived factor)
CD4
Provirus
ssRNA
Reverse
transcriptase
dsDNA
Macrophage-tropic (Nonsyncitium
inducing)
CCR5:
RANTES (regulated
on activation, normal
T cell expressed and
Secreted),
MIP1a, MIP1b
(Macrophage
Inflammatory
Protein)
Serological Profile
Kuby, 2007
Host Factors influencing course
 Transmission of HIV
 Sexual contact
 Breast feeding
 Transfusion
 During birth
 Sharing needles
 Resistance to HIV in individuals
 CCR5D32
 Some HLA types (HLA-A2 are resistant; HLA-B35 are
susceptible)
Virus-induced effects on immune cells
 Th Cells
 Initially control viral load
 Destruction of infected Th cells by CTL
 Cytopathic virus
 Anergy of surviving Th cells
 CTL
 gp120 specific CTL
 Virus mutation induces resistance to CTL
 Lack of Th affects CTL activation
 Resistance to CTL by downregulation of class I MHC on target cells
 Ab
 Develops after 3 weeks
 Virus Agic variability
 Non-neutralizing. Thus, ineffective
Immunomodulation
 HAART + IL-2 (To reconstitute the immune system)
 Chemokine receptor inhibitors
 Vaccines: Proteins, DNA, subunit and recombinant virus (SIV-HIV
chimeric virus )
Problems
 HIV-1 inf. -> AIDS in the presence of Abs
 Low immunogenicity
 Destruction of CD4+ T cells by vaccine
 Integration of virus in host genome
 Instability of HIV-1 genome
 High rate of virus replication (109 viruses/day)
 Live attenuated or heat killed organism (vaccinia virus carrier for
HIV proteins)
 Route of exposure (Rectal or vaginal challenge)
 Lack of animal models and in vitro testing system
Summary
 Primary immunodeficiencies are inherited
 They can affect hematopoietic stem cells,
lymphoid or myeloid cells.
 Secondary immunodeficiencies are due to
infections, aging, cancer or chemical exposure
 HIV affects immune system by eliminating
CD4+ T cells
 Vaccine development has been hindered by lack
of an experimental model, antigenic variation,
etc.