• 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.

Immunodeficiency Disorders

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

• Aetiology and symptoms • Classification and major features • Immunodeficiency characteristics • Immunodeficiency Evaluations

Immunodeficiency Disorders

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 DISEASES Cl assi ficat ion of Immunodef 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 Disease

)/ Brut on’ s

• 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.

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

Brutons Disease cont

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

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.

Com mon Vari abl e I mmunodef ici ency Di sease (CV ID)

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

Disorder characterized by a deficiency in

Severe Combined Immunodeficiency Disease (S CI D)

• 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.

• 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.

Selecti ve I gA def ici ency (IgA D)

• 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 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.

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.

IgAD cont

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 ) recessive progressive Autosomal

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 αfetoprotein levels • Patients may benefit from gamma globulin infusions. • Therapy includes gamma globulin if IgG or IgG subclass deficiency identified.

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.

Wi skott- Ald rich Syndrome (W AS)

T cell dysfunction manifests by
• Severe herpex virus and Pneumocystis carinii infections • Increased lymphomas and autoimmune diseases. • Prophylactic immunoglobulin administration and • Bone marrow transplantation.

WAS cont

• Patients benefit from

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 nitrobluetetrazolium 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).

• 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.

Acqui red I mmunodef ici ency S yndr ome (AIDS)

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

Principle mode of transmission through

HI V Tr ansm is sion

• 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.

STIs increase risk of transmission and infection

HIV Transmission cont

• 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) acute retroviral infection (ARI)

and

Stage 2 Stage 3

Loss of weight (< 10% of body weight); minor mucocutaneous infections; herpes zoster and recurrent upper respiratory tract infections (URTI) 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 HIV wasting syndrome; extrapulmonary tuberculosis; Pneumosystis carinii pneumoniae, Candidiasis of the oesophagus, trachea, brochi or lungs; toxoplasmosis of the brain, cryptosporidiasis

Stage 4

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 antiHIV effector mechanisms; HIV-infected Th2 response down regulates receptor CCR5 in favour of HIV co-receptor CXCR4.

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.

Polyclonal B Activat ion

Cell

AIDS patients with marked CD4+T cell depletion show

CD 4 T Cel l Depl eti on

• 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.

Major pulmonary illness in HIV-infected/ AIDS patients include

Pulm on ary Inf ecti ons

• 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)

• 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 nonspecific 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.

Auto imm une D isorders

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.

• 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.

Major neurological illnesses

Damage to neurons mediated by

Neuronal Damage cont

• CTL • Inappropriate production of IL1, IL-6, TNF-α and platelet derived factor (PAF) by HIVinfected macrophages. • NO, ROI, RNI, leukotreines and prostaglandins

• Malignancies of HIV disease result from immunodeficiency, aberrant cytokine production and activation of oncogenic viruses. AIDS-defining malignancies include

Mal ignanci es

• 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.

• Involves mainly macrophagemonocyte lineage cells and neutrophils. • Macrophages functionally immunodeficiencies • Antigen presenting capacity • Chemotaxis deficiency and cytokine production • Phagocytic and metabolic oxygenation activities (microbicidal and tumouricidal mechanisms)

PH AGO CYT IC CELL IMMU NODE FI CI EN CY

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.

• Intrinsic phagocytic enzymatic deficiency in intracellular killing of pathogens • X-linked cytochrome B • NADPH or NAPH oxidase •Glutathione peroxidase •Flavorprotein enzymes.

Chronic Gr anulo mato us Dis ease (C GD)

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

• 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 cont

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

• 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. .

Late Compl ement Component Def ici ency

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 Component C1q C3 C4A/B C5, 6, 7 and 8 C9 Properdin Factor H Factor 1 C1 inhibitor DAF(Decay) Accelerating factor) Disease Association Collagen vascular disease, SLE, bacterial infections Bacterial infections, glomerulonephritis Collagen vascular disease, autoimmune disease (SLE, PBC, autoimmune hepatitis, scleroderma) Recurrent Nesserial infections Recurrent Neisserial infections, SLE Fulminant Neisserial infections, sepsis Neisserial infections, glomerulonephritis, hemolytic uremic syndrome (HUS) Meningitis, pyogenic infections Hereditary angioneurotic eodema (HANE)
Paraxysmal nocturnal hemoglobinuria (PNH)

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.

Evaluations of Immunodeficiency

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.

• 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.

Pha goc yti c C el l Def icie ncy

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 HIVantigen specific, cytokine secreting T cells. • Immunophenotyping to identify responding CD3+,CD4+, CD8+ T cells

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