You are on page 1of 112

Immunodeficiency

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

Secondary B cell immunodeficiency


Selective IgG deficiency
Selective IgA deficiency
Primary T cell immunodeficiency
Di George syndrome
Ataxia - telangiectasia
Wiskott – Aldrich syndrome
Secondary T cell immunodeficiency
Acquired immunodeficiency
Lymphoproliferative diseases
Phagocytic immunodeficiency
Chemotaxis deficiency
Phagocytosis deficiency
Oxidative metabolic deficiency
Chronic granulomatous disease
Chediak-Higashi syndrome
Leukocyte adhesion deficienc

Complement system deficiency


C1q, C1r and C1s deficiency
C1-esterase inhibitor deficiency
C3 deficiency
C5, C6, C7, C8 deficiency
Aetiology
• Aetiology associated with
• Genetic defects of missing
enzymes (adenosine deamine) or
proteins (complement component
deficiency)
• Specific development impairment
(pre-B-cell failure)
• Primary immunodeficiency
• Infections, malnutrition and drugs
leading to
Aetiology cont
• Normal immune system
impaired through
• Loss or increased catabolism of
immune components eg
• Protein losing enteropathy,
• Nephritis syndrome and burns lead
to secondary immunodeficiency.
Aetiology cont
Primary B Cell Immunodeficiency
• Resides at the level of B cell
differentiation defect.
• Severe combined immunodeficiency
• Due to a failure of stem cells to
differentiate into pre-B cells.
• X-linked agammaglobulinaemia (XLA),
• Pre-B cells fail to convert into
immature B cells expressing SmIg.
Primary B Cell Immunodef cont
• Common variable
immunodeficiency associated
with
• Mature B cells failure to
differentiation into mature
plasma secreting cells
(antibody forming cells).
Primary ID cont
• Evaluation of antibody
deficiencies through immunization
using
• Tetanus toxoid,
• Diphtheria toxoid and
• Pneumococcal polyccharide
derived vaccines.
X-linked A ga mmaglobulinaemia (XLA )/ Brut on’ s
Disease
• Deficiency of B cell tyrosine kinase
causing failure in the development of
pre-B cell maturation to B cells.
• Bruton’s tyrosine kinase (BTK) gene
mutated in a vast majority of boys
diagnosed with XLA.
• Majority of XLA patients show
• Profound hypogammaglobulinaemia
involving all immunoglobulin classes
with <1% B cells in normal peripheral
blood.
Bruton’s Disease cont
• Absence of circulating mature
B cells, plasma cells
• Limited antibody production.
• Most frequent abnormality
∀µ heavy chain gene on
chromosome 14.
Brutons Disease cont
Clinical presentations of XLA
• Increased susceptibility to
encapsulated recurrent pyogenic
bacteria (S. pneumonia, H.
influenza type b and Pseudomonas
species)
• Skin infections (group A
streptococci and S. aureus)
• Persistent viral or parasitic
infections
XLA Clinical Presentations cont
• Males less than one year
present with unusually severe
and/or recurrent otitis media
• Sinopulmonary infections and
pneumonia with decreased B
lymphocytes and normal cell
mediated functions.
Brutons Disease cont
• Infants and adults are associated
with autoimmune diseases and
diarrhoea caused by G. lamblia.
• Patients are susceptible to
viruses that replicate in the
gastrointestinal tract and then
spread to CNS.
• Patients show low levels of IgG
and absence of IgM, IgA and IgE.
Hyper Ig M synd rome ( HIGM)
Dysgammaglobulinaemia type I (X-linked
primary immunodeficiency)
characteristics
• Normal or elevated levels of IgM with
complete absence of other
immunoglobulins.
• Patients (boys) afflicted with
recurrent bacterial and respiratory
infections, diarrhoea, otitis media and
neutropenia.
• Defect in CD40L on CD4 T cells leads to
• Failure of signals to IgM+ B cells
switch to IgA or IgG isotypes.
HIGM cont
• Syndrome characteristics
• Very high levels of IgM,
• Low levels of IgG without IgA.
• Autoimmunity occurs leading to
• Anaemia and failure in intracellular
killing by neutrophils
Com mon Vari abl e I mmunodef ici ency
Di sease (CV ID)
Heterogenous immunodeficiency
syndrome characterized by
• Hypogammaglobulinaemia
abnormalities (autoimmune
diseases and malignancy)
• Disorder associated with
• Low levels of Igs particularly too
few IgA and frequent bacterial
infections involving ears,
sinuses and airways.
CVID Manifestations
Common manifestations
• Chronic/recurrent infections of the
respiratory and gastrointestinal
tracts eg
• Giardia lamblia and bacterial
overgrowth occurs in the bowel
with increased inflammatory bowel
disease and gluten-sensitive
enterophathy
CVID cont
• Recurrent pyogenic infections
chiefly caused by S.pneumoniae
and H. influenzae.
• Differentiation of B cells to
plasma cells appears impaired.
• Patients show markedly
reduced levels of total Igs
particularly IgG (<200 mg/dL).
CVID cont
• Ig levels in CVID are often variable
• Do not appear to correlate with the
clinical symptoms of the disorder.
• Diagnosis of CVID
• Measurement of IgG and IgA levels
and
• Antibody responses to
immunization antigens
Severe Combined Immunodeficiency Disease
(S CI D)
Disorder characterized by a deficiency in
• Both B and T lymphocyte
functions with markedly low IgG,
IgA and Iglevels.
• SCID associated with
• Children failure to thrive, chronic
respiratory,
• Gastrointestinal and/or cutaneous
infections particularly recurrent viral,
bacterial, fungal and protozoan
infections in 6 months' infants.
SCID cont
• SCID manifests early with
• Persistent and recurrent
diarrhoea, otitis, thrush
and respiratory infections
in the first few months of
life.
SCID cont
• T cell defects associated with
• Candidiasis, CMV infection, measles
and varicella leading to life
threatening pneumonia, meningitis
and sepsis.
• SCID managed through Ig infusion,
stem cell transplantation and gene
replacement.
Omann Syndrome
Autosomal recessive gene
disorder
• Characterized by severe
eczematoid dermatitis
• Eosionophilia and elevated serum
IgE levels.
Se condary B Cell
Im mu nodefic iency Diseases

• Associated with defect in the


production of immunoglobulins.
• Deficiency selective,
• Only certain isotypes or sub-classes
of Igs involved.
• Infectious agents may be
responsible for the induction of
the disorders.
Selecti ve I gA
def ici ency (IgA D)
• Patients with IgAD have
• IgA levels < 5mg/dL with normal
levels of other Igs and
• 50% have chronic otitis, sinusitis or
pneumonia.
• IgA committed B lymphocytes
• Fail to mature into IgA-secreting
plasma cells caused by intrinsic B
cell defect
• Inadequate or defective CD4 T cell
help and suppressor CD8 T cells or
maternal anti-IgA antibodies.
IgAD cont
• Specific IgA deficiency occurs
in
• Body secretions and mucous
membranes lining the
airways and digestive tract.
• A strong HLA disease
association exists
• HLA - A2, B8 and Dw3.
IgAD cont
• IgAD associated with
• Normal B lymphocytes,
• Normal CD4+ and CD8+ T
cells and usually anti-IgA
autoantibodies;
• IgG subclass deficiency and
antibody deficiency to
pneumococcal immunization.
IgAD cont
• Patients susceptible to
• Allergic (conjunctivitis, urticaria
and asthma);
• Autoimmune and neurological
disorders,
• Various gastrointestinal
diseases (food allergy);
recurrent sinopulmonary
infections.
IgAD cont
Patients with selective IgA antibodies
associated with
• Recurrent viral and bacterial
sinopulmonary infections;
• Chronic mucocutaneous candidiasis;
• Autoimmune disorders and
immediate type hypersensitivity
reactions.
• IgAD patients at greater risk of
developing severe blood transfusion
reactions.
• Primary IgAD usually permanent.
Sel ectiv e IgG subcl ass
def ici enc y
• Homozygous deletions of major
part of Ig heavy chain
• Results in the absence of
individual IgG subclasses (IgG2,
IgG4)
• Direct cause-effect correlation
hasn’t clearly been demonstrated
and
• Overall IgG levels may be
normal.
IgG Subclass deficiency
Selective IgG subclass diseases
commonly associated with
• Recurrent pyogenic sinopulmonary
infections, principally
pneumococci and influenza.
• Total Ig levels may be normal and
specific IgG subclass markedly
low in the patients.
Selective IgG Deficiency
• Selective IgG4 associated
with
• Recurrent infections and
brochiectasis
• Transient hypogammaglobulimia
in infancy
• Low levels of IgG produced at 5
-6 months of age.
T Cel l Immunodef ici ency
Di seases
• T cell congenital disorders display
• Little or no cell mediated
immunity and may involve B cell
deficiencies.
• Patients particularly susceptible
• To repeated fungal (Candida)
• Protozoan and viral infections.
Primary T cell immunodefiency syndromes

• 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

Cli nic al s ta ges Ma jor c lin ic al


fe atu res Stage 1 Asymptomatic;
persistent generalized lymphodenopathy (PGL) and
acute retroviral infection (ARI)
Stage 2 Loss of weight (< 10% of body weight);
minor mucocutaneous infections; herpes zoster and
recurrent upper respiratory tract infections (URTI)
Stage 3 Loss of weight (>10% of body weight);
chronic diarrhoea(> 1 month); prolonged fever; oral
candidiasis; oral hairly leukoplakia; pulmonary
tuberculosis; severe bacterial infections and
vulvovaginal candidiasis
Stage 4 HIV wasting syndrome; extrapulmonary
tuberculosis; Pneumosystis carinii pneumoniae,
Candidiasis of the oesophagus, trachea, brochi or
lungs; toxoplasmosis of the brain, cryptosporidiasis
Immunopathol ogi cal
Mechani sms
HIV infected patients progress to
AIDS disease in three phases
Early phase lasts about 2 weeks
accompanied by
• Fever, aches and fluke-like
symptoms with high levels of
virus in blood;
Middle phase lasting months or
several years (latent) with
• Anti-HIV antibodies (4-8 wks
seroc
• Continuous depletion of CD4 T
cells killed by CD8+ CTL and
Late phase (AIDS)
• Rapid decline in CD4 T cells,
• Opportunistic infections including viral (herpes
simplex, herpes varicella zoster, EBV), bacterial
(M. tuberculosis), fungi (Candida-thrush) and
protozoan (Microsporidia)
• Cancers (lymphoma; Kaposi’s sarcoma) develop
• Th1 shift to Th2 response leads to inhibition of
HIV IgG neutralizing antibody
• Activation of IgE response that suppresses anti-
HIV effector mechanisms;
• HIV-infected Th2 response down regulates
receptor CCR5 in favour of HIV co-receptor
CXCR4.
Polyclonal B Cell
Activat ion
B cells polyclonal activation by HIV
derived mitogens leads to
• Non-specific
hypergammaglobulinnaemia.
• Polyclonal Ig increase, neutralizing,
virus-enhancing and ADCC
antibodies demonstrable.
• No correlation with clinical stages
of HIV infection in asymptomatic as
compared to AIDS patients.
CD 4 T Cel l Depl eti on
AIDS patients with marked CD4+T cell depletion
show
• Increased levels of serum IgE
antibodies and eosinophilia.
Depletion of CD4 T cells due to
• Formation of syntia between infected
and uninfected CD4+ T cells
• FasL CTL mediated apoptosis of Fas
positive infected CD4 cells.
• Class I HLA restricted CD8+ CTL, NK/K
cell mediated cytotoxicity
CD4 T Cell Depletion cont
• Absence of thymic replacement,
• Hyperactivation and exhaustion of
helper T cells,
• HIV-induced inhibitory activities and
autoimmune associated reactions.
• Progression of HIV disease and the
profound depletion in CD4 lymphocyte
subpopulations
• Associated with HLA- A1, B8, Cw7
and DR3 haplotypes.
Pulm on ary Inf ecti ons
Major pulmonary illness in HIV-infected/
AIDS patients include
• M. tuberculosis with potential
multidrug resistance and
Pneumocystis pneumonia common
when CD4 T cells <200/μ1
• TB in advanced HIV infection often
presents atypically with
extrapulmonary diseases affecting
• Bone marrow, bone,
• Urinary and gastrointestinal tracts
• Liver, regional nodes and the central
nervous system (CNS).
Gastrointestinal illness
• HIV-infected patients have an
inflammation of the lining of the
oesophagus (oesophagitis) often due to
• Fungal (candidiasis) or viral (herpex
simplex or cytomegalovirus)
infections.
• Chronic diarrhoea also occurs that
may be caused by bacteria
(Salmonella, Shigella, Listeria or
Escherichia coli) and
• Parasitic infections or rare
opportunistic infections including
• Cryptosporidiosis, microsporidiosis,
• Mycobacterium avium complex (MAC)
Auto imm une D isorders
• Autoimmune diseases manifest later in HIV
infections/AIDS.
• In antibody mediated diseases, HIV-infected
patients commonly associated with
• HIV infection of macrophage-monocyte
lineage cells enhance production of
cytokines like IL-1 and IL-6 causing non-
specific stimulation of B cells.
• Lymphotoxins and TNF may damage CD8+
T suppressor cells and thereby reduce their
regulation of B cells leading to
proliferation of anti-self B cells and
generation of autoantibodies.
• Antiself B cells may be activated by EBV,
CMV or HIV infections.
Molecular mimicry
Between HIV gp 120 and the Fab
portion of IgG may
• Cause antibody mediated
autoimmune thrombocytopenic
purpura.
Circulating immune complexes
associated with HIV antigens
• Deposited on vessels walls leading
to vasculitis.
In cell-mediated diseases, HIV-infected
patients associated with CD8+ cell
infiltration of distal organs eg in
Sjogren's syndrome and
myocardium in cardiac myositis.
Major neurological illnesses
• Toxoplasma encephalitis of the brain
caused by Toxoplasma gondii,
progressive multifocal
leukoencephalopathy (PML), a
demyelinating disease,
• Crytococcal meningitis caused by
fungus Cryptococcus neoformans and
AIDS dementia complex (ADC).
• HIV strongly neurotropic and the
infection leads to neurosychiatric
disorders in AIDS patients.
• Monocyte-macrophage lineage cells in
the brain and CTL found in CSF of
patients infected with HIV including
glial cells.
Neuronal Damage cont
Damage to neurons mediated by
• CTL
• Inappropriate production of IL-
1, IL-6, TNF-α and platelet
derived factor (PAF) by HIV-
infected macrophages.
• NO, ROI, RNI, leukotreines and
prostaglandins
Mal ignanci es
• Malignancies of HIV disease result from
immunodeficiency, aberrant cytokine production
and activation of oncogenic viruses.
AIDS-defining malignancies include
• Kaposi’s sarcoma caused by Kaposis
sarcoma associated herpes virus (KSHV)
presenting as purplish nodules of the
skin, mouth, gastrointestinal tract and
lungs.
• HIV-infected patients are at risk of
developing Hodgkin’s disease, anal and
rectal carcinomas.
• High grade B cell lymphomas (Burkitt’s
lymphoma) present in HIV-infected
patients and cervical cancer caused by
human papillinomavirus (HPV).
Malignancy Mechanism
Chronic HIV antigen stimulation of T cells and B cells
increases
• Production of cytokines (IL-1, IL-2, IL-4, IL-5,
IL-6 and IL-10)
• Activate B-cells which proliferate leading to
development of adenopathy,
• In non-Hodgkin's lymphomas, activation of
the oncogens and inactivation of the p53
tumours suppressor gene are demonstrable.
• A strong linkage between EBV and HIV
infection associated with tumour
development.
PH AGO CYT IC CELL
IMMU NODE FI CI EN CY
• Involves mainly macrophage-
monocyte lineage cells and
neutrophils.
• Macrophages functionally
immunodeficiencies
• Antigen presenting capacity
• Chemotaxis deficiency and
cytokine production
• Phagocytic and metabolic
oxygenation activities
(microbicidal and tumouricidal
mechanisms)
Neutrophil Deficiency
• Inherited neutrophil
dysfunctions
• Chronic granulomotous
disease
• Disorders of chemotaxis
• Defects of granulation and
leukolyte adherence
deficiency.
Phagocytic Cell Def cont
• Activation of macrophages leads
to liberation of IL-1 and TNF
• Results in stimulation of
hypothalamic thermoregulatory
centre.
• Detection and measurement of
urinary neopterin levels may
• Indicate in vivo macrophage
activation.
Chem otaxis Def ici ency
Depressed migration of monocytes
occurs in
• Newborn infants
• Patients under corticosteroid
• Other immunosuppressive
therapy,
• Diabetic and AIDS patients.
Chemotaxis deficiency
• Migration evaluated by chemotaxis
test dependent on a gradient of
chemoattractants (C5a, bacteria
products, leukotrienes and IL-1
• Chemotaxis defiency may be
secondary to expression of cell
surface receptors (C3b - R and
Fc-R).
Ph agocyt osis
De fic ie ncy
• Impairment in phagocytic function of
mø may occur in leukaemia, DLE and
other congenital conditions.
• Defect might be secondary to either
• Opsonic antibody deficiency or
• Failure in C3b-R and Fc-R
expression by the phagocytes.
Chronic Gr anulo mato us Dis ease
(C GD)
• Intrinsic phagocytic
enzymatic deficiency in
intracellular killing of
pathogens
• X-linked cytochrome B
• NADPH or NAPH oxidase
•Glutathione peroxidase
•Flavorprotein enzymes.
CGD cont
• Results in impaired heroxe
monophosphate shunt and
•Decreased reactive
oxygen intermediate
production (H2O2 and
superoxides).
CGD cont
• Professional phagocytes posses
membrane-associated NADPH-oxidase
system inactive in resting cells.
• Oxidase activation associated with
assembly of membrane-bound and
cytosolic constituents of the oxidase
system.
• Microbicidal oxidants major host
defence mechanism against infection.
• May cause damage to tissues in
inappropriate inflammation
CGD cont
• Clinical syndrome typically presents as
• Recurrent abscess formation
beneath the skin and associated
with
• Recurrent, severe staphylococci and
enteric (pyogenic) bacteria (S.
aureas Pseudomonas ) or fungal
infections (Candida and Aspergillus)
and phagocytic dysfunctions.
• Abscesses form in the organs of
mononuclear phagocytic system
(liver, lungs, spleen and lymph
nodes)
CGD Diagnosis
• Diagnosis of CGD involves
• Defective reduction of nitroblue
tetrazolium salt (NBT test);
• Impaired chemiluminescence or
superoxide production.
CGD diagnosis cont
Evaluations of quantitative abnormality in
neutrophil functions include
• Chemotaxis adhesion,
• Aggregation, phagocytosis,
granular content and
degranulation,
• Respiration burst activity and
intracellular bacterial killing.
Chedi ak - Higashi Syndrome
(CH S)
• Rare childhood autosomal
recessive inherited disorder
characterized by
• Hypopigmentation of the skin
and eyes (oculo cutaneous
albinism) and
• Hair (granules containing
melanin not made properly in
the skin giving pigmentary
differences in patients)
CHS cont
• Easy bruisability and prolonged
bleeding
• Recurrent infections commonly
involving the skin, lungs and
respiratory tract usually due to
Staphylococcus aureus,
Streptococci and Pneumococci
species
• Common neurological defects and
early death.
CHS cont
A neutrophil intracellular granule
defect affecting
• Vesicle synthesis
• Fusion or trafficking and/or
• Maintenance of storage/secretory
granules including various
leukocytes.
• Lysosomes of granulocytes and
fibroblasts dense bodies of
platelets and
• Azurophilic granules of neutrophils
CHS complications
• Often fatal in childhood through
• EBV infection or accelerated
lymphomalike lymphocyte,
• Progressive neurological
dysfunction and death.
• Diagnostic hallmark
• Occurrence of giant granules or
inclusion bodies in granulocytes and
neutropenia
Leukocyte Adhesion Deficie ncy
(L AD)
• Disorder of phagocytes results
• Inability to adhere and respond to
chemotactic factors for migration into
sites of infection and inflammation.
• Patient leukocytes lack receptors
for
• C3 and integrin molecules and
• Susceptible to recurrent bacterial
infections of the skin, subcutaneous
and deep tissues.
Complement Deficiency
Cl assi cal pathway def ici enc ies
• Cl-esterase inhibitors (CIINH)
deficiency associated with
• Hereditary angioedema leading
to recurrent episodes of
angioedema.
• Discoid or systemic lupus
erythematosus is associated with
complete C4 deficiency.
• C2 deficiency associated with skin
and joint manifestations
C3 Deficiency
• Patients have recurrent infections
especially gram-negative bacteria.
• C3 deficiency leads to poor
chemotactic and bacteriacidal
activities of the complement
cascade.
• Ineffective opsonization of
pathogens present with
• Severe recurrent pyogenic
infections principally caused by
meningococci and pneumococci.
Al tern ative Pathway
Def ici enc ies
• Usually deficiency of properdin,
factor B and D rare.
• Properdin deficiency associated
with
• Increased encapsulated bacterial
infections
• History of invasive meningococcal
disease,
• Pneumococci and haemophilus
infection
Late Compl ement Component
Def ici ency
• C5, C6, C7, C8 and C9 deficiencies
associated with
• Inability to form MAC and
susceptibility to recurrent
pyogenic infections.
• Patients present with
meningococcal meningitis or
extragenital gonococcal
infections. .
MBL Pathway Deficiency
• Individuals have higher propensity
for severe and repeated infections in
early life.
• Lung function significantly reduced
in carriers of MBL deficiency.
• C3 nephrit is fa ctor (C 3Nef)
defi ciency
• Associated with mesangiocapillary
glomerubonephritis.
Complements System Deficiency and Disease Associations
Deficient Disease Association
Component
C1q Collagen vascular disease, SLE, bacterial
infections
C3 Bacterial infections, glomerulonephritis
C4A/B Collagen vascular disease, autoimmune disease
(SLE, PBC, autoimmune hepatitis, scleroderma)
C5, 6, 7 and 8 Recurrent Nesserial infections
C9 Recurrent Neisserial infections, SLE
Properdin Fulminant Neisserial infections, sepsis
Factor H Neisserial infections, glomerulonephritis,
hemolytic uremic syndrome (HUS)
Factor 1 Meningitis, pyogenic infections

C1 inhibitor Hereditary angioneurotic eodema (HANE)


DAF(Decay) Paraxysmal nocturnal hemoglobinuria (PNH)

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

You might also like