Professional Documents
Culture Documents
Disorders
• Im mu nodefic ie ncy dis orders
associa ted wi th
• Defe ct o r im pairm ent in i mmune
fu nctio n o r
• Absence e .g. c ongenita l,
acquire d o r
• In duced t hro ugh i nfections a nd
various enviro nme ntal fa ctors.
Manifestations
• Dis ord ers ma nife st a t diffe rent
le vels in clu din g
• B c ell , T c ell , p hagocytic c ell s
and c ompleme nt s ys tem.
• Ge netic imm unodefic ie ncies
• Most promi nent manif estati ons:
dermatol ogi cal condit ions
eg ecze ma a nd c uta neous
in fe ctio ns
Immunodeficiency
Disorders
• Aetiology and symptoms
• Classification and major
features
• Immunodeficiency
characteristics
• Immunodeficiency
Evaluations
Congenital Disorders
• Cl oned genes eg
•Chroni c
granul omatous
di sease
•X- lin ked
im munodefi ci enci es
and
•Myel operoxi dase
defi ci ency
Symptoms
• Recurrent respiratory infections,
• Persistent bacterial infections
leading to complications
(sinusitis, chronic otitis and
bronchitis)
• Increased susceptibility to
opportunistic infections (OIs) and
recurrent fungal yeast infections
Symptoms cont
• Skin and mucous membrane
infections
• Resistant thrush, oral ulcers
and conjunctivitis
• Diarrhoea and malabsorption
• Failure to thrive and delayed or
incomplete recovery from
illness.
Classification of IDDs
Pri mar y B cell immun od efi ci ency
X-linked agammaglobulinaemia (XLA)
Hyper- IgM syndrome
Common variable immunodeficiency
Severe combined immunodeficiency
Se co nd ary B ce ll immu no de fi cien cy
Selective IgG deficiency
Selective IgA deficiency
Pr ima ry T cel l immu no def icienc y
Di George syndrome
Ataxia – telangiectasia
Wiskott – Aldrich syndrome
Se co nd ary T ce ll immu no de fi cien cy
Acquired immunodeficiency
Lymphoproliferative diseases
Ph ag oc yti c immu no defici enc y
Chemotaxis deficiency
Phagocytosis deficiency
Oxidative metabolic deficiency
Chronic granulomatous disease
Chediak – Higashi syndrome
Leukocyte adhesion deficiency
Co mpl emen t sy st em def ici enc y
C1q, C1r and C1s deficiency
C1- esterase inhibitor deficiency
C3 deficiency
C5, C6, C7, C8 deficiency
C3b – R and 4b – R expression defienciency
IMMUNODEFICIENCY
Cl assi ficat ion of ImmunodefDISEASES
ici ency
Primary B cell immunodeficiency
Di seases X-linked agammaglobulinaemia (XLA)
Hyper-IgM syndrome
Common variable immunodeficiency
Severe combined immunodeficieny
• Di-George syndrome,
• Wiskott-Aldrich syndrome,
• Cartilage hair hypoplasia,
• Ataxia - telangiectasia,
• Defective expression of class II
MHC molecules and
• Defective expression of CD3-T cell
receptor (TCR) complex
Di George Syndrome (Thymi c
Apl asi a)
Congenital disorder characterized
by
• Lack of embryonic development
or underdevelopment of the 3rd
and 4th pharyngeal pouches
• Associated with thymic
hypoplasia, hypothyroidism and
congenital heart disease.
Di George Syndrome
• Maternal alcoholism may lead to Di George
syndrome.
• Patients susceptible to uncontrolled
opportunistic infections.
• Profoundly impaired in cellular
mechanisms.
• Profound lymphopenia (T cell <1200µL)
• Defective T cell mitogenic or allogenic
cell responses occur.
Thymic Aplasia cont
• Parathyroid hormoneabsent and
hypocalcemia common.
• Calcium and parathyroid hormone
administration beneficial.
• Effective treatment through
• Foetal thymic transplantation
with an under 14 week foetal
thymus.
Atax ia Tela ng iecta sia
(AT )
Autosomal recessive progressive
neurodegenerative childhood disorder
associated with
• Lack of coordination (cerebella
ataxia) and dilation of facial blood
vessels (telangiectasis) and slurred
speech
• Patients have defective mechanisms
of DNA repair and are predisposed to
leukaemias and lymphomas
• Extremely sensitive to radiation
exposure and susceptible to chronic
respiratory infections.
AT cont
• A deficiency of IgA, IgM and/or IgG
subclasses demonstrated.
• Chronic sinopulmonary infections
major and related to neurological
abnormalities.
• Diagnosis confirmed with elevated α-
fetoprotein levels
• Patients may benefit from gamma
globulin infusions.
• Therapy includes gamma globulin if IgG
or IgG subclass deficiency identified.
Wi skott- Ald rich
Syndrome (W AS)
An X-linked recessive disorder
associated with thyrombocytopenia
and eczema.
• Patients have
• Elevated IgA and IgE
• Low IgM
• Variable T cell dysfunctions
• Impaired response to
polysaccharide antigens resulting
• In recurrent pyogenic bacterial
infections usually affecting ears,
sinuses and lungs.
WAS cont
T cell dysfunction manifests by
• Severe herpex virus and
Pneumocystis carinii infections
• Increased lymphomas and
autoimmune diseases.
• Patients benefit from
• Prophylactic immunoglobulin
administration and
• Bone marrow transplantation.
Chronic Mucocuta neous
Candidia sis (C MC )
• Characterized by an
• Increased susceptility to
chronic Candida albicans
infection and
• Strongly associated with
endocrinopathy.
• Patients display T cell
dysfunctions and often develop
fungal infections in the skin and
mucous membranes.
CMC cont
• Hodgkin's disease, severe
combined immunodeficiency
common
• Hypoparathyroidism common
followed by Addison's disease
•Usually main cause of death
in CMC infected patients
CMC cont
• Immune defects in CMC patients
mainly associated
• Selective T cell unresponsiveness to
Candida antigens with an intact B
cell antibody response.
• T cell responses to irrelevant
antigens (mitogens and allogenic
responses) usually normal or
equivocable.
Diagnosis of CMC
• Culturing Candida albicans from
cutaneous lesions in order to
identify the fungus.
• T cell responses to candida
antigen usually impaired.
• Phagocytic and chemotatic
activity of macrophages and
neutrophil reduction of nitroblue-
tetrazolium salt defective.
SEC OND ARY T CE LL
IMMU NODEFI CIEN CIES
• Normal immune system altered or
impaired or decreased thru
• Malnutrition
• Viruses (HIV) and X-rays
• Cytotoxic drugs (cancer diseases
lymphoproliferative chemotherapy)
• Corticosteroids (leukaemias and
lymphomas)
• Aging
Secondary T Cell Def
• Most important secondary
immunodeficiency:
• Acquired immunodeficiency
syndrome (AIDS)
• Caused by human
immunodeficiency virus
(HIV).
Acqui red I mmunodef ici ency S yndr ome
(AIDS)
• HIV-1 predominantly found in East,
Central, South and W. Africa
• HIV-2 reported mainly in W. Africa.
• Characterization of HIV-1 revealed
• HIV sub-types A, C, D in East
Africa
• Subtype B and E found in
Western countries and Thailand,
respectively.
HIV Clades
• HIV-0 subtype been
documented.
• HIV clades M, N and O
•Most common human
cases caused by
members of group M.
HI V Tropis m
• Depletion of CD4+ expressing
cells (T cells, APCs) by HIV
• CCR5 and CXCR4 major HIV-1
coreceptors for R5 and X4 strains,
respectively,
• Both strains coexist usually
during infection
• X4 strains appear to dominate in
the final stages of AIDS.
HIV Tropism cont
• HIV binds both CD4 and either
coreceptor with gp 120
• Triggers an allosteric change in
a second molecule, gp 41 that
• Penetrates the host plasma
membrane facilitating virion
entrance into the cell.
HIV Tropism cont
Penetration of host plasma
membrane results into virion
• Entrance with reverse
transcriptase and integrase
molecules attached to viral RNA.
• Reverse transcriptase synthesizes
DNA copies of RNA
• Enter the nucleus where the
integrase catalyses their
insertion into the host DNA
chromosome.
HIV replication cont
• HIV DNA transcribed into
new RNA molecule
• Enters the cytosol and
translated by host
ribosomes.
HIV Proteins
HIV Replication
HI V Tr ansm is sion
Principle mode of transmission through
• Homosexual and heterosexual
practices
• Sharing of contaminated
needles
• Unscreened transfused blood
and products
HIV transmission cont
• Infected organs or tissue
transplants and vertically in
newborns of HIV-infected
mothers.
• Both intrauterine and
intrapartum transmission of
HIV infection may occur, from
the mother either in utero or
at birth.
HIV Transmission cont
STIs increase risk of
transmission and infection
• Cause the disruption of the
normal epithelial barrier by
genital ulceration and/or
microulceration or by
• Accumulation of HIV
infected lymphocytes and
macrophages in semen and
vaginal secretions.
HIV Transmission cont
A higher risk of two to six folds due to
• Genital ulcers caused by syphilis
and/or chancroid, gonorrhoea,
chlamydia infection and
trichomoniasis cause local
accumulation of lymphocytes and
macrophages.
• Male circumcision appears to confer
resistance to HIV
Mother to Chi ld Tr an smiss ion
(MTCT)
• Occurs in utero during the last
few weeks of pregnancy and at
child birth.
• MTCT during pregnancy, labour
and delivery high
• Declining transmission rates
from 25% to 1.5% attributed to
single-dose of nevirapine (NVP).
• NVP – resistance associated
with subtype D than subtype A.
MTCT cont
Major maternal risk factors for breast
milk transmission associated with
• Low CD4+ cell counts,
• Maternal albumin and low
haemoglobulin values
• High plasma and cervical HIV
levels
• High levels of HIV RNA and gp 120
– specific IgG in breast milk.
HIV Infection/AIDS Staging System
Accelerating
factor)
Evaluations of Immunodeficiency
B c ell (a ntib ody) d efi ciency
• Primary pathogens detected
• Gram-positive organisms
(pneumococci, streptococci, and
haemophilus) at about 6 months
onset.
• Total Ig levels <200 mg/dL after
immunization with
• Tetanus toxoid; H. Influenza type B
vaccine
• Pneumococcal/meningococcal
vaccine.
IgG Subclass Deficiency
Diagnosed when after age of 2
yrs
• IgG1 level <250 mg/dL, IgG2
<50mg/dL and IgG3<25mg/dL
or undetectable IgG4 levels.
• SmIg positive (CD19, CD20)
• Normal B cells 5-10% of PBL.
Pha goc yti c C el l
Def icie ncy
• Primary pathogens
• Recurrent staphylococcal,
Klebsiella and gram-negative
bacterial infections.
• Absence of nitroblue tetrazolium
(NBT) blue formazan in the dye
reduction test
• Indicates chronic
granulomatous disease.
Phagocytic Evaluation
• Measurement of phagocytosis
using
• Latex particles or bacteria by
neutrophils or with
• Monocytes/macrophages.
• Granulocyte assays for
• Hydrogen peroxide and superoxide
production
T C el l Defi ci ency
• Primary pathogens found in T cell
deficiency
• Intracellular bacterial, viral,
protozoan and fungal opportunistic
infections.
• Absence of DTH skin erythema and
induration
• Detected (<5mm) at 48 hr after
immunization with mumps, Candida
and tetanus toxoid antigens in over 2
yrs individuals.
• CD4 T cell count are <200 cells/µL and
CD4/CD8 ratio <1.0.
T Cell Deficiency
• Identification of activated cell
markers: CD25, NK cells CD16 and
CD56 and thymocytes, CDI
• T cell function assays
• Lymphokine production (γ-IFN, IL-2)
• Proliferative responses to antigen or
mitogen stimulation
• Cytotoxicity tests performed.
Evaluations in HIV infected/AIDS
Patients
• CTL determined using
• Chromium release assays that
detect the ability of CD8+ T cells
to lyse target cells expressing
specific HIV antigens.
• IFN-γ production measured by
• Capacity of T cells to secrete
the cytokine in response to a
specific HIV antigen based on
ELISpot assay.
HIV Evaluation cont
• In intracellular cytokine staining
(ICS)
• Flow cytometry-based method
used in the enumeration of HIV-
antigen specific, cytokine
secreting T cells.
• Immunophenotyping to identify
responding CD3+,CD4+, CD8+ T
cells