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Immunodeficiences
Autoimmunity – system attacks host
cells and tissues
 Hypersensitivity- unfavorable immune
response
 Immunodeficiency – system fails to
protect

 Primary immunodeficiency
○ Genetic or developmental defect
 Secondary immunodeficiency - acquired
Mechanisms of Immunodeficiency
Loss or reduction of:
 Cell type
 Cell numbers
 Cell function




Deficient humoral immunity usually results in
increased susceptibility to infection by encapsulated,
pus-forming bacteria and some viruses,
whereas defects in cell-mediated immunity lead to
infection by viruses and other intracellular microbes.
Combined deficiencies in both humoral and cell
mediated immunity make patients susceptible to
infection by all classes of microorganisms.
Immunodeficient patients, especially those with
defects in cellular immunity, often present with
infections by microbes that are commonly
encountered but effectively eliminated by healthy
persons; such infections are said to be opportunistic.
Defects in innate immunity can result in different
categories of microbial infections, depending on
the pathway or cell type affected.
 Complement deficiencies, for instance, resemble
antibody
deficiencies
in
their
clinical
presentation,
 Natural killer (NK) cell deficiencies result mainly
in recurrent viral infection.

Primary Immunodeficiencies
Lymphoid Immunodeficiences

Combined – effects both B and T cells

B-cell Immunodeficiency
○ Range from absence of B cells, plasma cells,
immunoglobulins to absence of only certain
classes of Abs
○ Subject to bacterial infections but do well
against viral since T-cell branch is ok

T-cell Immunodeficiency
○ Can effect both humoral and cell-mediated
Progenitor
Progenitor
• Defects in the cell mediated system are
associated with:
 increased susceptibility to viral, protozoan,
and fungal infections. Intracellular pathogens
such as Candida albicans, Mycobacteria are
often implicated, reflecting the importance of T
cells in eliminating intracellular pathogens.
also affect the humoral system, because of
the requirement for T-H cells in B-cell
activation. particularly in the production of
specific antibody
Defect in T Cell
Combined
partial B & T
cell defect
Defect in cells that
are critical to the
development or
activation of T cell
(APC)
Reduced
MHC I
molecules
Decrease
No. of
functional
CD8+ & NK
Reduced
MHC II
molecules
Decrease No.
of functional
CD4+
Defects in thymic
development
(abnormal
embryonic changes)
Prevent
thymic
education
of T cell
Defect in T cell development
Progenitor
Progenitor
B and T-cell deficiency divided into these categories:
A. Selective T-cell deficiency:
Disease
Defect
Clinical manifestation
DiGeorge
syndrome
Thymic aplasia
Depression of T cell number
with absence of responses.
MHC class I
deficiency
Failure of TAP 1
molecule to
transport peptide
to endoplasmic
reticulum
Defects in
transcription
factors.
1.CD8+ T cell def.
2.CD4+ T cell normal.
3. Recurrent viral infection.
4.Normal Ab formation.
MHC class II
def(Bare
lymphocyte
syndrome)
1.def of CD4+ T cell.
2. Hypogammagloulinemia.
3.Clinically as SCID.
Ataxia
telangiectasia
Defect in kinase 1. gait abnormality.
involved in the 2. Telangectasia (capillary distortion
cell cycle.
in the eye).
3.def of IgA & IgE production.
C. Complete functional B and T cell deficiency:
Sever combined Defects in common 1. Opportunistic (fungal)
ID(SCID).
γ chain of IL-2 infection.
receptor.
2. Low level of circulating
lymphocyte.
Primary Immunodeficiencies
Combined Immunodeficiencies

Thymus
○ DiGeorge Syndrome – decreased or absent
thymus
- Results from deletion of region on chromosome 22
in developing embryo, developmental anomaly
- third and fourth pharyngeal pouches during fetal
life.
- Lowered T cell numbers, results in B cells not
producing sufficient Abs
MHC DEFICIENCY class I deficiency
(Bare lymphocytes syndrome I or TAP- 1 or 2
deficiency):
defect in their transport associated
protein (TAP) gene and hence do not
express the class-I MHC molecules and
consequently are deficient in CD8+ T
cells , CD4+ normal
 recurrent viral infection , normal DTH,
normal Ab production

MHC DEFICIENCY class II deficiency
(Bare lymphocytes syndrome II):
Due to defect in the MHC class II
transactivator protein gene, which results
in a lack of class-II MHC molecule on APC.
 Patients have fewer CD4 cells ,
immunoglobulin levels decreased owing to
defective T-cell help
 Increased susceptibility to infection

Combiend partial B- and T-cell
deficiency
Ataxia-telangiectasia:
Defect in kinase involved in cell cycle
 Associated with a lack of coordination of
movement (ataxis) and dilation of small blood
vessels of the facial area (telangiectasis).
 T-cells and their functions are reduced to
various degrees.
 B cell numbers and IgM concentrations are
normal to low.

Primary Immunodeficiences
Combined Immunodeficiences

Severe Combined Immunodeficiency
(SCID)
○
○
○
○
Low # of circulating lymphocytes
Non-proliferating T cells
Thymus doesn’t develop
Usually fatal early years of life
- Infant will have viral and fungal infections
- Bacterial don’t show up until later because of
placental transfer of Abs from mother
- Chronic diarrhea, pneumonia, lesions
○ Many genetic defects can contribute to
SCID
○ Defects in common γ chain of IL-2 receptor.
Defects in B-cell function due to
Early B
cell
maturation
blocked
Isotype
switching
dose not
occur
Terminal
differentiati
on of B cell
blocked
T-cell to B-cell
is defective
Defect in T cell development
Progenitor
Progenitor
Examples for humoral immunity defects.
Disease
Bruton Xlinked
hypogamma
gloulinemia
Molecular
defect
Symptoms/signs
Def of
tyrosine
kinase so
blocks Bcell
maturation
1.Low Ig of all classes.
Def of
X-linked
hyper-IgM CD40L on
activated
syndrome
T cell
2. No circulating B cell.
3.B-cell maturation
stopped at pre-B stage.
4. Normal CMI.
Treatment
1.Monthly
gammaglobulin
replacement.
2.Antibiotic.
1.Higher serum titer
Antibiotic &
of IgM only. 2. Normal gammaglobulin
B & T cell number. 3.
.
Susceptibility to EC
bacteria &
opportunists.
Disease
Molecular
defect
Symptoms/signs
Treatment
Selective IgA Deficienc Repeated
Antibiotic,
deficiency
y of IgA sinopulmonary & GIT not Ig.
infections.
Common
Unknown 1.onset in late teens. Antibiotics
variable
2.B cell present in
immunodef
peripheral blood.
3.Ig level decrease
with time.
4.increase
autoimmunity & atopy
Primary Immunodeficiences
B cell Immunodeficiences

X-linked Agammaglobulinemia
○ B cell defect
- Defect in kinase that keeps B cells in pre-B stage
○ Low levels of IgG and absence of other
classes
○ Recurrent bacterial infections
Primary Immunodeficiences
Combined Immunodeficiences

X-linked Hyper-IgM Syndrome
○ Deficiency of IgG, IgE, IgA but elevated levels
of IgM
○ Defect in T cell surface marker CD40L
- This is needed for interaction between TH and B
cell for class switching for T-dependent antigens
- T independent antigens are not effected therefore
there is production of IgM
CD40 ligand
B
Th
CD40
ligand
Cytokines - IL-4, 5, 6
Primary Immunodeficiences
B cell Immunodeficiences

Common Variable Immunodeficiency
(CVI)
○ Low levels of immunoglobulin –
hypogammaglobulinemia
○ Manifests later in life
Primary Immunodeficiences
B cell Immunodeficiences

Selective Deficiences of Immunoglobulin
Classes
○ IgA deficiency is most common
 Recurrent respiratory and urinary tract infections,
intestinal problems
○ IgG deficiencies are rare
 Can often be treated by administering
immunoglobulin
Defect in phagocytic cells (Myeloid):
(phagocytes, neutrophils,)
 Defects are significant because of their key role
in innate and adaptive I.R.
 affect both
ability to kill microb
( Chronic granulomatous disease,
Chediak-higashi syndrome )

interactions with other cell
(Leukocyte adhesion defect 1)
Defect in T cell development
Progenitor
Progenitor
Defects of phagocytic cells
Disease
Molecular defect(s)
Symptoms
Chronic
granulomatous
disease(CGD).
Def of NADPH oxidase;
failure to generate
superoxide anion & other
O2 radicals, so the
microorganisms will be
ingested but not killed.
Leukocyte
adhesion
deficiency(LAD
Absence of CD18(LFA-1) Recurrent
&
(leukocyte integrins).
chronic infections,
Chediak-Higashi
Syndrome
Defect in organelle membrane
which inhibits normal fusion of
lysosomes
Fail to destroy ingested
microbes
Recurrent
infections
with
catalase-positive
bacteria & fungi.
fail to form pus.
Recurrent infection with
bacteria (chemotactic and
degranulation
defects,
absent NK activity
Chronic Granulomatous
Disease (CGD)
Defect in enzymes and microcidal
molecules (NADPH oxidase; failure to
generate superoxide anion & other O2
radicals)
 So the microorganisms will be ingested but
not killed
 Symptoms : recurrent infections with
catalase- positive bacteria and fungi
specially Staphylococcus aureus

Chediak- Higashi
Syndrome
Normal levels of enzymes(digestive)
 Defect in organelle membrane which
inhibits normal fusion of lysosomes
 Fail to destroy ingested microbes
 Symptoms : Recurrent infection with
bacteria (chemotactic and degranulation
defects, absent NK activity)

Leukocyte Adhesion Defect
1
( LAD-1)
β chain of
leukocyte integrin, and become un
able to migrate
 Symptoms : Recurrent and chronic
infection , fail to form pus

Absence of CD
18 –
common
Disorders of complement system
Due to
Classical
pathway
Both
pathway
Deficiencies in
complement
regulatory
proteins
Defects of complement.
Components
Deficiency
Signs/diagnosis
Classic pathway
C1q,C1r,C1s, 1.Marked increase in immune
C4,C2
complex disease.
2.Increased infection with pyogenic
bacteria.
Both pathways
C3
1.Recurrent bacterial infection.
2.Immune complex disease.
C5,C6,C7,C8 Recurrent meningococcal &
gonococcal infections.
Def of regulatory C1-INH
proteins.
(hereditary
angioedema)
1.Overuse of C1,C4 or C2.
2.Edema at mucosal surfaces.
Defect in classical pathway
Deficiencies of the classical pathway
C1q, C1r, C1s, C4, or C2
 Result in a propensity to develop
immune complex diseases such as SLE
because it required for the dissolution
of immune complexes
 Increasing the risk of immune
complex diseases SLE and increased
infections with pyogenic bacteria

Deficiencies in complement
regulatory proteins




The most important deficiency of the complement
system is C1 inhibitor which is responsible for
dissociation of activated C1 by binding to C1r2 C1s2
Deficiency result in Hereditary angioedema (HAE)
The low level of C1 inhibitor in the plasma leads to
increased activation of pathways that release
bradykinin, the chemical responsible for the increased
vascular permeability, and the pain seen in individuals.
Patients have recurrent
Episodes of swelling at
mucosal surfaces
Treatments for Immunodeficiency

Replacement of missing protein
○ Administering immunoglobulin
○ Express genes in vitro (in bacteria) for
cytokines

Replacement of missing cell type
○ Bone marrow transplantation

Replacement of missing or defective
gene
○ Gene therapy
Secondary or Acquired
Immunodeficiencies





Agent-induced immunodeficiency: e.g. infections
including HIV
Metabolic disorders and trauma
Splenectomy
Drugs such as corticosteroids, cyclosporin A,
radiation and chemotherapy
Aging
Human Immunodeficiency Virus







Is a member of genus retrovirus (RNA virus)
belonging to Lentiviridae
Characterized by long incubation period and slow
course of disease
HIV-1 (Common in US) and HIV-2 (in Africa)
AIDS patients have low CD4+ T cells
Virus prevalent in homosexual, i.v. drug users,
transfusion, infants born to infected mothers
(prenatally, during birth and lactationally)
Opportunistic infections with Candida albicans,
Pnuemocystis carinii, Mycobacterium avium, etc.
Patients with HIV have high incidence of cancers
such as Kaposi sarcoma and lymphomas
Oral Candidiasis (Thrush)
Kaposi Sarcoma
HIV strains are:
(T-tropic strains) because it infect T cell and the
receptor called CXCR4.
(M-tropic strains) with receptor called CCR5 functions
for the monocyte or macrophage.
Pathogenesis of HIV Infection
and AIDS
HIV disease begins with acute infection,
which is only partly controlled by the
host immune response, and advances to
chronic
progressive
infection
of
peripheral lymphoid tissues .
 The virus typically enters through
mucosal epithelia. The subsequent
events in the infection can be divided
into several phases.

Death
Opportunistic
infections
<200CD4+
T cells/mm
Mechanisms of Immunodeficiency
Caused by HIV

HIV infection ultimately results in impaired
function of both the adaptive and innate
immune systems. The most prominent
defects are in cell-mediated immunity, and
they can be attributed to several
mechanisms, including direct cytopathic
effects of the virus and indirect effects.
An important cause of the loss of CD4+ T
cells in HIV infected individuals is the direct
effect of infection of these cells by HIV.
 Depletion and functional impairment of
these cells in HIV-infected individuals by
chronic activation of the T cells may predispose
the cells to apoptosis. Apoptotic death of
activated lymphocytes may account for loss of T
cells greatly exceeds the numbers of HIVinfected cells.

HIV-specific CTLs are present in many
patients with AIDS, and these cells can
kill infected CD4+ T cells.
 In addition, antibodies against HIV
envelope proteins may bind to HIVinfected CD4+ T cells and target the
cells for antibody-dependent cellmediated cytotoxicity.

Immunological abnormalities associated with HIV
infection in different stages
•1. T HELPER (TH) CELLS:
Early: No in vitro proliferative response to specific antigen
Late: Decrease in TH-cell numbers and corresponding helper
activities; no response to T-cell mitogens or alloantigens
•2. ANTIBODY PRODUCTION:
Early: Enhanced nonspecific IgG and IgA production but
reduced IgM synthesis
Late: No proliferation of B cells specific for HIV-1: no
detectable anti-HIV antibodies in some patients; increased
numbers of B cells with low CD21 and enhanced Ig secretion.
•3. CYTOKINE PRODUCTION:
Early: Increased levels of some cytokines
Late: Shift in cytokine production from TH1 subset to TH2
subset
•4. DELAYED-TYPE HYPERSENSITIVITY
Early: Highly significant reduction in proliferative capacity of
DTH cells and reduction in skin-test reactivity
Late: Elimination of DTH response; complete absence of
skin-test reactivity
•5. T CYTOTOXIC (TC) CELLS
Early: Normal reactivity
Late: Reduction but not elimination of CTL activity due to
impaired ability to generate CTLs from TC cells
Diagnosis
RT-PCR (Reverse transcriptase –Polymerase
Chain reaction) – detects viral load
 ELISA (Enzyme linked immunosorbent assay)

 Abs against HIV proteins (sensitive and specific)

Western Blot
 Ab detection
Infected individuals who have developed Abs
(2 wks-6 months after infection)
Positive
Vaccinated

CD4+:CD8+ T cell counts
Abs are ineffective to control HIV
!!!
Virus grows intracellularly
 Abs develop after ~2 weeks. Thus cannot
be used as a diagnostic test initially
 Abs are not neutralizing

Refferences :
 Immunology , Kuby, seventh edition
 Medical microbiology, Jawetz, 26th
edition
 Cellular and Molecular Immunology,
Abul K. Abbas, 8th edition.
