Imunodefisiensi Imunodefisiensi

Evy YunihastutiEvy Yunihastuti

Immunodeficiency andImmunodeficiency andAutoimmunityAutoimmunity

Evy YunihastutiEvy Yunihastuti

ImmunodeficiencyImmunodeficiency

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ImmunodeficiencyImmunodeficiency

• Primary Primary ImmunodeficiencyImmunodeficiency– Neutrophil defectsNeutrophil defects– Humoral: B cell Humoral: B cell

defectsdefects– Humoral: ComplementHumoral: Complement– Cell-mediatedCell-mediated:: T cells T cells– Severe combined Severe combined

immunodeficiencyimmunodeficiency

• Secondary Secondary ImmunodeficiencyImmunodeficiency– AIDSAIDS– NeutropeniaNeutropenia

• Post-transplantPost-transplant• BMTBMT• chemotherapychemotherapy

– Splenectomised Splenectomised patientpatient

Immunodeficiency in adultsImmunodeficiency in adults

Infectious disease: HIV

Infectious disease: HIV

Environmental stress

Environmental stress

Age extremes: old age

Age extremes: old age

Surgery & trauma, splenectomy

Surgery & trauma, splenectomy

Immunosuppresive drugs *

Immunosuppresive drugs *

malnutritionmalnutrition

Genetic and metabolic disease

Genetic and metabolic disease

Adaptive & innate

IMMUNITY

Adaptive & innate

IMMUNITYIMMUNODEFICIENCY

IMMUNODEFICIENCY

INFECTIONINFECTION

TUMORTUMOR

*20 mg or more per day of prednisone, 14 days or longerNOT aerosols, alternate day, short courses, topical

Chinen J, Shearer.WT. Secondary immunodeficiency. J Allergy Clin Immunol 2010; 125: S195-202 , Epidemiology and Prevention of Vaccine-Preventable Diseases. National Center for Immunization and Respiratory Diseases. CDC. Revised April 2009.

Body surfaces and their resident Body surfaces and their resident microbial floramicrobial flora

The immunodeficient hostThe immunodeficient host

• Virulent infection with common Virulent infection with common organism (e.g. TB)organism (e.g. TB)

• Infection with opportunistic pathogenInfection with opportunistic pathogen– virus (cytomegalovirus - CMV)virus (cytomegalovirus - CMV)– bacteria (bacteria (Mycobacterium avium Mycobacterium avium

intracellulare)intracellulare)– fungi (aspergillus, candida, pneumocystis)fungi (aspergillus, candida, pneumocystis)– protozoa (cryptosporidia, toxoplasma)protozoa (cryptosporidia, toxoplasma)

Immunodeficient patients Immunodeficient patients are…are…• More susceptible to infection and diseaseMore susceptible to infection and disease

• More likely to develop persistent infectionMore likely to develop persistent infection

• More likely to develop multiple infectionsMore likely to develop multiple infections

• may develop unusual clinical may develop unusual clinical manifestations, i.e. which are not seen in manifestations, i.e. which are not seen in immunocompetent patientsimmunocompetent patients

Acquired Immunodeficiency Acquired Immunodeficiency NeutropeniaNeutropenia

• Timely admission in cyclical chemotherapyTimely admission in cyclical chemotherapy– <0.5 x 10<0.5 x 1099/l risk of infection/l risk of infection– <0.1 x 10<0.1 x 1099/l high risk of septicaemia/l high risk of septicaemia

NeutrophilsX 109/l

Time (days)

Cytotoxic

0.50.1

Onset maximum risk

2 4 6 8 10 12

Major clue Major clue categories in categories in suspected suspected infection in infection in patients who patients who areareimmunocomprimmunocompromised.omised.

Opportunistic Infection Percentage (%)

Candidiasis oral 50

Pulmonary TB 37

Pneumonia 16.5

Extra pulmonary TB 13.8

Toxoplasma encephalitis 12.1

Chronic Diarrhea 11.2

Seborrheic dermatitis. 5.3

CMV retinitis 3.4

Candidiasis esophageal 3.3

Persistent Fever 3.2

Herpes zoster 3.2

EPP 1.6

Wasting syndrome 1.2

Herpes simplex 0.6

Cryptococcal Meningitis 0.4

ITP 0.2

Toxocariasis 0.1

PCP 0

Pattern of opportunistic infections of newly diagnosed HIV-infected patients in Ciptomangunkusumo hospital 2008-2009

Karjadi TH, Yunihastuti E , Pramundita R, Aziza S, Lie S, Imran D, et al.Presented at 2010 PDPAI Clinical Research Meeting

Defects in immunity suggested by Defects in immunity suggested by infectioninfection

Phagocytes

Non Specific immunity

LymphadenitisSkin infectionLiver, lung abscessGI disease, UTI

BacteriaStaphylococci, E colliKlebsiellaFungi: candida, aspergillus

Bacteria: salmonella, proteus

ComplementClassic-alternate

Systemic bacterial infectionAutoimmune disease

Pyogenic bacteria: StaphylococciNeisseria

Virus: CMV, HSV

Defence system

Infectious complication

Common microorganism

Less common

Defects in immunity suggested by Defects in immunity suggested by infectioninfection

B cells antibody

Specific immunity

Respiratory tract sespisGI tract sepsis

Pyogenic bacteriaStaphylococciStreptococciHaemophilus

EnterovirusOther bacteria: salmonella

T cells cellular immunity

Viral infectionGastroenteritisLymphoproliferation

Virus: CMV, adeno, HSVPyogenic bacteriaFungi: candida, aspergilus, PCPProtozoa: cryptospora

Other bacteria

Defence system

Infectious complication

Common microorganism

Less common

Opportunistic infection and CD4 cell Opportunistic infection and CD4 cell countcount

Temporal relationship of stem-Temporal relationship of stem-cell transplantation with cell transplantation with complicationscomplications

Timeline of posttransplant infections Timeline of posttransplant infections following solid organ transplantationfollowing solid organ transplantation

Management of Management of immunodeficiencyimmunodeficiency

• Managing the causeManaging the cause

• Treatment and prevention of infectionTreatment and prevention of infection

• SupportiveSupportive

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HIV preferentially infect CD4+ T HIV preferentially infect CD4+ T cellscells

HIV

RNARNA

DNA

ds DNAds DNA

RT

Integrase

TranscriptionTranscription

Proviral DNAProviral DNA

Spliced mRNASpliced mRNA

mRNAmRNA

Genomic RNA

PolyproteinProtein

Protease

1 2233

44

55vpr

HIV replicates in CD4HIV replicates in CD4

Type of HIV progressionType of HIV progression

A model of HIV pathogenesisA model of HIV pathogenesis

HIV-1 infection and replication

Main target CCR5+ activated CD4+ T cell

HIV-1 infection and replication

Main target CCR5+ activated CD4+ T cell

Systemic immune activationAdaptive and innate

Systemic immune activationAdaptive and innate

Massive CD4+ T cell depletion

In particular mucosal CD4+ T cell

Massive CD4+ T cell depletion

In particular mucosal CD4+ T cell

Bacterial Translocati

onIncl. TLR ligand

Bacterial Translocati

onIncl. TLR ligand

Viral reactivation

In particular CMV

Viral reactivation

In particular CMV

Anti-HIV immune responseCellular and

humoral

Anti-HIV immune responseCellular and

humoral

Production of HIV proteins

Gp120, nef

Production of HIV proteins

Gp120, nef

Exhaustion of immune responseDecline of regenerative

capacity loss of effective anti-HIV immunity

= Immunosenescence?

Exhaustion of immune responseDecline of regenerative

capacity loss of effective anti-HIV immunity

= Immunosenescence?

Inflammation-related disordersOsteoporosis

AtherosclerosisNeurocognity deterioration

Frailty

= inflammation-ageing?

Inflammation-related disordersOsteoporosis

AtherosclerosisNeurocognity deterioration

Frailty

= inflammation-ageing?

Sustained T-cell apoptosis

Turn over and senescence

Sustained T-cell apoptosis

Turn over and senescence

Secretion of proinflammatory

cytokinese.g. IL-6, TNFα, IL-1β

Secretion of proinflammatory

cytokinese.g. IL-6, TNFα, IL-1β

Persistence of this process

=> Collapse of immune system / AIDSPersistence of this process

=> Collapse of immune system / AIDS

Systemic immune activationAdaptive and innate

Systemic immune activationAdaptive and innate

Homeostatic mechanism

Cellular renewalhematopoesis

Homeostatic mechanism

Cellular renewalhematopoesis

DamageToLymphoidtissue

HIVreplication

HIVreplication

Prinsip penatalaksanaanPrinsip penatalaksanaan HIVHIV

SupoSuportifrtif

Infeksi Infeksi oportuoportunistiknistik

AntiretAntiretroviralroviral(ARV)(ARV)

02-200702-2007 LSU SVM PBSLSU SVM PBS 2525