This document discusses immunodeficiency disorders. It describes how deficiencies in antibodies, phagocytes, or complement components can lead to infections by extracellular bacteria. Deficiencies in cell-mediated immunity are associated with recurrent viral, protozoal, and fungal infections. Primary immunodeficiencies are caused by genetic defects, while secondary immunodeficiencies result from infection, toxicity, radiation, or other acquired factors. Specific primary immunodeficiencies that affect B cells, T cells, phagocytes, or the complement system are described. The document also discusses acquired immunodeficiency syndrome (AIDS) caused by HIV, outlining the virus structure, pathogenesis, clinical features, and diagnosis.

1. IMMUNODEFICIENCYIMMUNODEFICIENCY
DISORDERSDISORDERS
Dr.CSBR.Prasad, M.D.Dr.CSBR.Prasad, M.D.
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2. Infectious consequences ofInfectious consequences of
immunodeficiencyimmunodeficiency
 Antibody deficienciesAntibody deficiencies
 Phagocyte deficienciesPhagocyte deficiencies oror
 Complement deficienciesComplement deficiencies
are associated with infections with extracellular pyogenicare associated with infections with extracellular pyogenic
bacteria (Pneumonia, Otitis media & skin infections)bacteria (Pneumonia, Otitis media & skin infections)
 Deficiencies of CMIDeficiencies of CMI
are associated with recurrent chronic viral, protozoal andare associated with recurrent chronic viral, protozoal and
fungal infectionsfungal infections
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3.  Primary immunodeficiencyPrimary immunodeficiency
 Secondary immunodeficiencySecondary immunodeficiency
Origins of ImmunodeficiencyOrigins of Immunodeficiency
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4. Origins of ImmunodeficiencyOrigins of Immunodeficiency
 Primary or CongenitalPrimary or Congenital
Inherited genetic defects in immune cellInherited genetic defects in immune cell
development or function or inherited deficiencydevelopment or function or inherited deficiency
in a particular immune moleculein a particular immune molecule
 Secondary or AcquiredSecondary or Acquired
A loss of previously functional immunity due toA loss of previously functional immunity due to
infection, toxicity, radiation, splenectomy, aginginfection, toxicity, radiation, splenectomy, aging
or malnutritionor malnutrition
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8. Primary immunodeficienciesPrimary immunodeficiencies
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9. B cell deficienciesB cell deficiencies
 Congential hypogammaglobulinemiaCongential hypogammaglobulinemia
- Symptoms at 9months to 2yrs of ageSymptoms at 9months to 2yrs of age
- Treat with IV immunoglobulins (IVIG)Treat with IV immunoglobulins (IVIG)
 Hyper IgM - defective CD 40 lignad expressionHyper IgM - defective CD 40 lignad expression
 Selective IgA deficiencySelective IgA deficiency
- 1:600 to 1:800 persons1:600 to 1:800 persons
- Increased sinopulmonary infections & allergiesIncreased sinopulmonary infections & allergies
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11. T cell deficienciesT cell deficiencies
 Congenital Thymic aplasiaCongenital Thymic aplasia
 Chronic mucocutaneous candidiasisChronic mucocutaneous candidiasis
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12. Severe combined immunodeficiencySevere combined immunodeficiency
 X-linked SCIDX-linked SCID
- Defect in IL-2 receptor- Defect in IL-2 receptor
 Swiss type SCIDSwiss type SCID
- ADA deficiency- ADA deficiency
 Bare Lymphocyte syndromeBare Lymphocyte syndrome
- Absence of class-II MHC gene products- Absence of class-II MHC gene products
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13. Phagocytic deficienciesPhagocytic deficiencies
 Chronic Granulomatous DiseaseChronic Granulomatous Disease
- NADPH oxidase defect- NADPH oxidase defect
 Chediak-Higashi syndromeChediak-Higashi syndrome
- Abnormal lysosome formation- Abnormal lysosome formation
 Leucocyte Adhesion DeficiencyLeucocyte Adhesion Deficiency
- Absence of leucocyte adhesion molecules- Absence of leucocyte adhesion molecules
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14. Complement deficienciesComplement deficiencies
 Single component deficienciesSingle component deficiencies
- C3 deficiency- C3 deficiency
 Hereditary angioneurotic edemaHereditary angioneurotic edema
- C1 inhibitor deficiency- C1 inhibitor deficiency
 C5, C6, C7, C8 or C9 DeficiencyC5, C6, C7, C8 or C9 Deficiency
- Recurrent bacterial meningitis due to defective- Recurrent bacterial meningitis due to defective
membrane attack complexmembrane attack complex
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15. Primary immunodeficienciesPrimary immunodeficiencies
 ADA deficiencyADA deficiency
 X-Linked AgammaglobulinemiaX-Linked Agammaglobulinemia
 Hyper-IgM SyndromeHyper-IgM Syndrome
 Isolated IgA DeficiencyIsolated IgA Deficiency
 Di George Syndrome (Thymic Hypoplasia)Di George Syndrome (Thymic Hypoplasia)
 Severe Combined Immunodeficiency DiseasesSevere Combined Immunodeficiency Diseases
 Wiskott-Aldrich SyndromeWiskott-Aldrich Syndrome
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18. Causes of AcquiredCauses of Acquired
ImmunodeficiencyImmunodeficiency
 CancerCancer
 Cytotoxic drugs / RadiationCytotoxic drugs / Radiation
 MalnutritionMalnutrition
 SplenectomySplenectomy
 Immunosuppressive therapyImmunosuppressive therapy
 Stress / emotionsStress / emotions
 Aging (thymic atrophy)Aging (thymic atrophy)
 InfectionsInfections
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19. ACQUIREDACQUIRED
IMMUNODEFICIENCYIMMUNODEFICIENCY
SYNDROMESYNDROME
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20.  IntroductionIntroduction
 At risk groupsAt risk groups
 Routes of transmissionRoutes of transmission
 HIV structureHIV structure
 Pathogenesis of HIVPathogenesis of HIV
 Clinical featuresClinical features
 Morphologic changesMorphologic changes
 Lab diagnosisLab diagnosis
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21. INTRODUCTIONINTRODUCTION
 Caused by retrovirus- humanCaused by retrovirus- human
immunodeficiency virus (HIV)immunodeficiency virus (HIV)
 Profound immunosuppressionProfound immunosuppression
 Opportunistic infectionsOpportunistic infections
 Secondary neoplasmSecondary neoplasm
 Neurologic manifestationsNeurologic manifestations
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22. AT RISK GROUPSAT RISK GROUPS
 Homosexual or bisexual menHomosexual or bisexual men
 Intravenous drug abusersIntravenous drug abusers
 HemophiliacsHemophiliacs
 Recipients of blood and blood componentsRecipients of blood and blood components
 Heterosexual contactsHeterosexual contacts
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23. ROUTES OF TRANSMISSIONROUTES OF TRANSMISSION
 Sexual transmissionSexual transmission
 Parenteral inoculationParenteral inoculation
 Passage of virus from infected mothers toPassage of virus from infected mothers to
their newbornstheir newborns
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24. STRUCTURE OF HIVSTRUCTURE OF HIV
 Major capsid protein –Major capsid protein –
p24p24
 Nucleocapsid protein –Nucleocapsid protein –
p7/p9p7/p9
 2 copies of genomic2 copies of genomic
RNARNA
 3 viral enzymes3 viral enzymes
(protease, reverse(protease, reverse
transcriptase, integrase)transcriptase, integrase)
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26. In this computer generated image, the large object isIn this computer generated image, the large object is
a human CD4+ , & the spots on its surface & thea human CD4+ , & the spots on its surface & the
spiky blue objects in the foreground represent HIVspiky blue objects in the foreground represent HIV
particlesparticles
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27. TYPES OF HIVTYPES OF HIV
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28. PATHOGENESIS OF HIVPATHOGENESIS OF HIV
There areThere are two major targetstwo major targets of HIV infection:of HIV infection:
 The immune system andThe immune system and
 The central nervous systemThe central nervous system..
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29. PATHOGENESIS OF HIVPATHOGENESIS OF HIV
 HIV -1 infects T cells & macrophagesHIV -1 infects T cells & macrophages
 Viral replication in the regional LNViral replication in the regional LN
 Viremia & widespread seeding of lymphoid tissueViremia & widespread seeding of lymphoid tissue
 Viremia is controlled by host immune response, soViremia is controlled by host immune response, so
patient enters a clinical latency phasepatient enters a clinical latency phase
 Partial viral replicationPartial viral replication
 Erosion of CD4 cellsErosion of CD4 cells
 CD4 numbers declineCD4 numbers decline
 Full blown AIDSFull blown AIDS
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32. HIV LIFE CYCLEHIV LIFE CYCLE
Entry- HIV can only replicate inside human cellsEntry- HIV can only replicate inside human cells
 gp120/CD4 bindinggp120/CD4 binding
 Conformational change in gp120Conformational change in gp120
 gp120/CD4 bind CCR-5 or CXCR-4gp120/CD4 bind CCR-5 or CXCR-4
 Conformational change in gp41Conformational change in gp41
 gp41 membrane penetrationgp41 membrane penetration
 Membrane fusionMembrane fusion
The contents of the HIV particle are then released into theThe contents of the HIV particle are then released into the
cell, leaving the envelope behindcell, leaving the envelope behind
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36. Reverse Transcription and IntegrationReverse Transcription and Integration
 Once inside the cell, enzyme reverse transcriptaseOnce inside the cell, enzyme reverse transcriptase
converts the viral RNA into DNA.converts the viral RNA into DNA.
 This DNA is spliced into the human DNA by theThis DNA is spliced into the human DNA by the
HIV enzyme integraseHIV enzyme integrase
 Once integrated, the HIV DNA is known asOnce integrated, the HIV DNA is known as
provirusprovirus
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37. Transcription and TranslationTranscription and Translation
 HIV provirus may lie dormant within a cell .HIV provirus may lie dormant within a cell .
 But when the cell becomes activated, it treats HIV genesBut when the cell becomes activated, it treats HIV genes
in much the same way as human genesin much the same way as human genes
 First it converts them into messenger RNA (using humanFirst it converts them into messenger RNA (using human
enzymes)enzymes)
 Then the messenger RNA is transported outside theThen the messenger RNA is transported outside the
nucleus, and is used as a blueprint for producing newnucleus, and is used as a blueprint for producing new
HIV proteins and enzymesHIV proteins and enzymes
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38. Assembly, Budding and MaturationAssembly, Budding and Maturation
 HIV genetic material + HIV proteins & enzymes formHIV genetic material + HIV proteins & enzymes form
new viral particles.new viral particles.
 Enzyme protease - cuts long strands of protein intoEnzyme protease - cuts long strands of protein into
smaller pieces, which are used to construct mature viralsmaller pieces, which are used to construct mature viral
corescores
 The newly matured HIV particles are ready to infectThe newly matured HIV particles are ready to infect
another cell.another cell.
 Once person is infected, they pass HIV to others in theirOnce person is infected, they pass HIV to others in their
body fluidbody fluid
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39. This electron microscope photo showsThis electron microscope photo shows
newly formed HIV particles buddingnewly formed HIV particles budding
from a human cellfrom a human cell
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40. An HIV particle budding from a cellAn HIV particle budding from a cell
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41. MECHANISM OF CD4 LOSSMECHANISM OF CD4 LOSS
Chronic T cell activationChronic T cell activation
 Viral replication in infected CD4 T cellsViral replication in infected CD4 T cells
death of infected cellsdeath of infected cells
 Activation of uninfected CD4 T cellsActivation of uninfected CD4 T cells
activation induced cell deathactivation induced cell death
 Expression of HIV peptides on infected CD4 TExpression of HIV peptides on infected CD4 T
cells killing of infected cells by virus specific CTLScells killing of infected cells by virus specific CTLS
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43. MAJOR ABNORMALITIES OFMAJOR ABNORMALITIES OF
IMMUNE FUNCTION IN AIDSIMMUNE FUNCTION IN AIDS
 LYMPHOPENIALYMPHOPENIA
 DECREASED T-CELL FUNCTION INDECREASED T-CELL FUNCTION IN
VIVOVIVO
 Loss of memory T cellsLoss of memory T cells
 Susceptibility to opportunistic infectionsSusceptibility to opportunistic infections
 Susceptibility to neoplasmSusceptibility to neoplasm
 Decreased DTHDecreased DTH
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44.  ALTERED T-CELL FUNCTION IN VITROALTERED T-CELL FUNCTION IN VITRO
 decreased specific cytotoxicitydecreased specific cytotoxicity
 decreased IL-2 and TNF-G productiondecreased IL-2 and TNF-G production
 POLYCLONAL B-CELL ACTIVATIONPOLYCLONAL B-CELL ACTIVATION
 HypergammaglobulinemiaHypergammaglobulinemia
 ALTERED MONOCYTE OR MACROPHAGEALTERED MONOCYTE OR MACROPHAGE
FUNCTIONSFUNCTIONS
 decreased chemotaxis & phagocytosisdecreased chemotaxis & phagocytosis
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45. NATURAL HISTORY OF AIDSNATURAL HISTORY OF AIDS
 An acute retroviral syndromeAn acute retroviral syndrome
 A middle, chronic phaseA middle, chronic phase
 Full-blown AIDSFull-blown AIDS
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46. SYMPTOMSSYMPTOMS
EARLYEARLY
 FeverFever
 HeadacheHeadache
 TirednessTiredness
 Enlarged lymph nodes (glands of the immuneEnlarged lymph nodes (glands of the immune
system easily felt in the neck and groin)system easily felt in the neck and groin)
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47. LATELATE
 Lack of energy & Weight lossLack of energy & Weight loss
 Frequent fevers and sweatsFrequent fevers and sweats
 Persistent or frequent yeast infections (oral orPersistent or frequent yeast infections (oral or
vaginal)vaginal)
 Persistent skin rashes or flaky skinPersistent skin rashes or flaky skin
 Pelvic inflammatory diseasePelvic inflammatory disease
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48. CNS INVOLVEMENTCNS INVOLVEMENT
 MeningoencephalitisMeningoencephalitis
 Aseptic meningitisAseptic meningitis
 Peripheral neuropathyPeripheral neuropathy
 AIDS-dementia complexAIDS-dementia complex
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49. OPPORTUNISTICOPPORTUNISTIC
INFECTIONSINFECTIONS
 Protozoal and helminthicProtozoal and helminthic
 FungalFungal
 BacterialBacterial
 ViralViral
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50. OPPORTUNISTIC INFECTIONSOPPORTUNISTIC INFECTIONS
BacterialBacterial MycTB, MAI Copmplex, SalmonellaMycTB, MAI Copmplex, Salmonella
ParasiticParasitic
Toxoplasma, CryptosporidiumToxoplasma, Cryptosporidium
Microsporidium, LeishmaniaMicrosporidium, Leishmania
FungalFungal
Pneumocystis carinii, CryptococcusPneumocystis carinii, Cryptococcus
neoformans, Candida, Histoplasmaneoformans, Candida, Histoplasma
Coccidioidis immitisCoccidioidis immitis
VirusesViruses Herpes, CMV, Varicella zoasterHerpes, CMV, Varicella zoaster
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51. X-ray- There is increased white (opacity) in the lower lungsX-ray- There is increased white (opacity) in the lower lungs
on both sides, characteristic ofon both sides, characteristic of PneumocystisPneumocystis pneumonipneumoni
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52. Hairy LeucoplakiaHairy Leucoplakia
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53. CryptococcosisCryptococcosis
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54. CryptococcosisCryptococcosis
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55. HistoplasmosisHistoplasmosis
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56. HistoplasmosisHistoplasmosis
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57. HistoplasmosisHistoplasmosis
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58. NEOPLASMSNEOPLASMS
 Kaposi’s sarcomaKaposi’s sarcoma
 B-cell non-Hodgkin’s lymphomaB-cell non-Hodgkin’s lymphoma
 Primary effusion lymphomasPrimary effusion lymphomas
 Primary lymphoma of the brainPrimary lymphoma of the brain
 Invasive cancer of uterine CxInvasive cancer of uterine Cx
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59. KAPOSI’S SARCOMAKAPOSI’S SARCOMA
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60. KAPOSI’S SARCOMAKAPOSI’S SARCOMA
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61. KAPOSI’S SARCOMAKAPOSI’S SARCOMA
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63. LAB DIAGNOSISLAB DIAGNOSIS
 SPECIFICSPECIFIC
 ELISA, western blot & IFELISA, western blot & IF
 Ag detection by recombinant DNA techniquesAg detection by recombinant DNA techniques
 INDIRECT TESTSINDIRECT TESTS
 CD4 & CD8 cell countsCD4 & CD8 cell counts
 Lymph node biopsyLymph node biopsy
 Platelet countsPlatelet counts
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66. When to suspect PrimaryWhen to suspect Primary
Immunodeficiency?Immunodeficiency?
 Recurrent infectionsRecurrent infections
 Recurrent Otitis mediaRecurrent Otitis media
 Recurrent infections by capsulated organismsRecurrent infections by capsulated organisms
 AspleniaAsplenia
 Absence of tonsilsAbsence of tonsils
 Absence of thymusAbsence of thymus
 Partial albinismPartial albinism
 HypocalcemiaHypocalcemia
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67. E N DE N D
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69. Hyper IgE Syndrome
- extremely high levels of IgE; often also IgD
- characteristic facies in children; dermatitis and pyogenic infections (staphylococci affecting
lungs, joints, skin: Job’s syndrome, after the Biblical sufferer). Respiratory allergies are rare, and
the dermatitis is quite distinct from that of the atopic form. Associate abnormalities in tooh root
resorbtion (not loosing the primary teeth). Reduced bone density (fractures). Very rare
autoimmunity and malignancies.
- elevated numbers of eosinophils in blood and sputum; some impairments in secondary
humoral responses, chemotaxis of neutrophils.
- some forms are autosomal dominant
- some associate defects in IgE catabolism
- some have low propensity in IFN gamma production by Th, but not increased IL-4; possible
mutations in the IL-4Ralpha receptor chain (common for IL-4 and IL-13) resulting in increased
signaling
- Antibiotics; surgery; no effect for IFNgamma or BMT/HCT
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70. Hyper-IgE syndromeHyper-IgE syndrome
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Hyper-IgE syndrome. Also known as Job syndrome, this immunodeficiency has a distinct facial
expression with mild asymmetry, prominent jaw, and wide nasal ala. Eczematous skin lesions, recurrent
staphylococcal skin infections, recurrent episodes of pneumonias often due to Staphylococcus aureus,
pneumatoceles, and mucocutaneous candidiasis are common.

71. Hyper IgM Syndrome
-5 types; the most common is secondary to CD40L-deficiency affecting Th cells
-HIGM2: autosomally inherited mutations in AID: in contrast with HIGM1, no hypermutation detectable and
different opportunistic infections (as CD40L is normal); abnormal giant CGs with many IgD and IgM harboring
B lymphocytes, enlarged lymphoid organs.
-HIGM3: autosomal recessive mutations CD40; very similar to X-linked HIGM1, with deficits of cell mediated
immunity
-HIGM4 - similar to, and milder than HIGM2, but impaired humoral immune responses (opportunistic bacterial
and mycobacterial infections). Hypermutation is not affected. CD40, CD40L, AID, UNG, NEMO are normal,
but defects downstream of CD40 signaling and DNA-repair prevent class switch
- HIGM5 - very similar to HIGM2, with susceptibility to bacterial (not opportunistic) infections. The defect lies
in uracil DNA glycosilase UNG, that acts downstream of AID, removing the uracil residues deaminated by AID,
removal that initiate the double-stranded breaks required for class switch.
- HIGM-NEMO (HIGM associated with X-linked hypohydrotic ectodermal dysplasia) is a mild form of HIGM;
sparse hair and abnormal or missing teeth, lack swat glands. Impaired responses to polysaccharides, but also of
cell-mediated immunity. Frequent opportunistic bacterial and mycobacterial infections. NEMO = NF-kappaB
essential modulator, part of the IKK (IbB kinase) complex that phosphorylates IkB - the inhobitor of the NF-kB.
That stands that NF-kB is involved in the CD40-indiced class switch, but details are still missing
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72. DiGeorge syndrome
-complex disorder affecting thymus genesis (~1:4 000
live births)
-abnormal facies (long narrow face, small mouth,
prominent nose, hooded or full upper eyelids, low-set
cupped ears), small hands, abundant hair on the head,
cardiac and renal malformations, cleft palate, neural
tube defects, parahypothyroidism, recurrent infections.
-translocations or large (2Mbp) deletions 22q1,
(sometimes associated with maternal alcoholism,
diabetes, chemicals), and possible TBX1 mutation, a
transcription factor involved also in aortal
development, GSCL (goosecoid-like) - involved in
neurogenesis, and HIRA, a corepressor involved in
embryonic histone transcription in heart, cranium,
pharyngeal arches.
-T cells, if present, display abnormal tendency to
spontaneous apoptosis. NK and B counts appear
normal
-murine equivalent: nude defect. DiGeorge syndrome. The characteristic facies of infants
with DiGeorge syndrome include widened epicanthal folds,
flattened nasal bridge, short philtrum, recessed chin, rounded
small mouth, and low set, posteriorly rotated ears with simplified
helices.
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76. SCID. This patient typifies the wasted infant with SCID
with failure to thrive and repeated infections. This patient has
no human leukocyte antigen/mixed leukocyte culture matched
siblings and at the time (circa 1970s) was not a candidate for a
mismatched bone marrow transplant. This child succumbed to
his infections.
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77. AT, Ataxia-Telangiectasia
-autosomal recessive, progressive cerebellar ataxia, oculocutaneous telangiectasia, variable CID
recurrent severe lung infections, sins infections, hypo IgA, IgE, IgG2, IgG4; hypersensitive to ionizing
radiation, increased risk of cancer (lymphomas, acute leukemias), autoimmunity.
Due to neurological defects, patients confined to weelchair before age 20, and die before 30. No effective
treatment.
Defects: in ATM gene (ataxia telangiectasia mutated), that encodes a PI3K family protein that
phosphorylated p53, thus preventing it’s interaction with Mdm2 and subsequent ubiquitin-directed
degradation.
Ataxia telangiectasia (AT). This patient demonstrates
facial cellulitis and periorbital telangiectasias. The AT mutated
gene produces pleiotropic changes in cellular response to
radiation, cell cycle control, and intracellular transport of
proteins that manifest themselves in choreoathetosis, cerebellar
ataxia, susceptibility to malignancies, and humoral and
cellular (T-cell) deficiency. Patients with AT frequently have
greatly elevated serum levels of a-fetoprotein due to defective
liver metabolism. Patient died at less than 10 years of age.
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78. WAS Wiscott-Aldrich Syndrome
-X-linked recessive heterogenous disorder, WAS protein gene.
WASP is expressed by all hematopoietic cells; is involved in HSC
survival.
~1/3 patients (classic WAS) CID, eczema, thrombocytopenia;
increased susceptibility to viral, pyogenic, opportunistic infecitons,
autoimmunity, allergy, lymphomas)
~1/5 patients: only some of the above (Thrombocytopenia, XLT)
WASP is critical for both lymphocyte and platelet survival. DTH
responses are affected; normal IgG but reduced IgM and elevated
IgA and E levels.
- unclear mechanism; WASP binds to SH3-containing signaling
molecules, Src kinases, Grb2 adaptor protein, PLC gamma, Btk,
nut also with the cytoskeleton (acting as direct effector of the
GTPase Cdc42, a regulator of the cytoskeleton organization). All
these are important in T cell activation.
IV-IG, splenectomy, BMT/HCT
Wiskott-Aldrich syndrome (WAS). Recurrent
bacterial,
fungal, and, in this case, viral (Herpes simplex)
infections
plague patients with WAS. Equally a problem
is that of
bleeding into eczematous skin lesions, mucosal
surfaces,
and other tissues because of concomitant
thrombocytopenia
and small platelet size. The long-term
prognosis is complicated
by an increased risk of malignancies and
autoimmune
disorders. Patient died at age of 14.
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