SECONDARY SECONDARY IMMUNE IMMUNE

DEFICIENCYDEFICIENCY

w.pongsak,MDw.pongsak,MD

scopescope

Extreme ageExtreme agemalnutritionmalnutritionMetabolic diseasesMetabolic diseases

- DM- DM

- uremia- uremiaSurgery and traumaSurgery and traumaEnvironmental conditionEnvironmental condition

IntroductionIntroduction

Primary vs secondary immune deficiencyPrimary vs secondary immune deficiency Most common cause of SID is…Most common cause of SID is… Complexity of SIDComplexity of SID What did you know about SID?What did you know about SID?

Extreme AgeExtreme Age

Newborn peroidNewborn peroidAdvanced ageAdvanced age

Newborn peroidNewborn peroid Neonate increase susceptibility to infection than older Neonate increase susceptibility to infection than older

childrenchildren Fewer marginal zone B cell & decrease CD 21 Fewer marginal zone B cell & decrease CD 21

expression on B cellsexpression on B cells Immature of 2Immature of 2ndnd lymphoid organ lymphoid organ Absent maternal IgG before 32 wks GAAbsent maternal IgG before 32 wks GA Defect in innate immunityDefect in innate immunity - decrease neutrophil storage pool- decrease neutrophil storage pool - decrease Neu. Function - decrease Neu. Function - decrease TLR signaling, cytokine production- decrease TLR signaling, cytokine production complementcomplement

Advanced ageAdvanced age Increase elderly in populationIncrease elderly in population Decline in immune system with ageDecline in immune system with age Impaired ability to respond to vaccine and to fight Impaired ability to respond to vaccine and to fight

infectioninfection Innate immunity & agingInnate immunity & aging Adaptive immunity & agingAdaptive immunity & aging Thymic involution Thymic involution CMV and immune senescence CMV and immune senescence

- aging=> CMV infection- aging=> CMV infection

- CMV infection => aging of immune- CMV infection => aging of immune

Robert R Rich . Clinical immunology 3 rd edition

Robert R Rich . Clinical immunology 3 rd edition

Innate immunity & agingInnate immunity & aging Neutrophil - oxidative burstNeutrophil - oxidative burst -- bactericidal activity bactericidal activity - Chemotaxis- Chemotaxis MMǾ - Phagocytic activityǾ - Phagocytic activity - Oxidative burst- Oxidative burst - MHC class II expression- MHC class II expression NK cells - Numbers of cellsNK cells - Numbers of cells - cytotoxicity- cytotoxicity - inflammatory cytokines- inflammatory cytokines - proliferative response to IL-2- proliferative response to IL-2

Adaptive immunity & agingAdaptive immunity & aging

T cell -T cell - naïve T cell count naïve T cell count - memory and effector T cell count- memory and effector T cell count - diversity of T cell repertoire- diversity of T cell repertoire - expression of costimulatory Mol.- expression of costimulatory Mol. - proliferation capacity- proliferation capacity - T cell signaling- T cell signaling - activation of naïve T cell- activation of naïve T cell

CD 28-CD8 T cells may be CD 27+ or - but CD 28-CD4 T cells limit to CD 27-=>loss of CD 40L

=Loss of co-stimulatory molecule

Thymic involution

B cells - generation of B cell precursorsB cells - generation of B cell precursors -- number of B1 cellsnumber of B1 cells - diversity of B cells repertoire- diversity of B cells repertoire - size and number of germinal center- size and number of germinal center - expression of costimulatory - expression of costimulatory moleculemolecule - antibody affinity- antibody affinity - isotype switching- isotype switching - specific antibodies for foreign - specific antibodies for foreign antigenantigen - serum antibodies specific self - serum antibodies specific self antigenantigen - stimulation of B cells by follicular - stimulation of B cells by follicular dendritic cellsdendritic cells

Vaccine in elderlyVaccine in elderly Protective efficacy partial loss in elderlyProtective efficacy partial loss in elderly Occur in both regular vaccine and new vaccineOccur in both regular vaccine and new vaccine New development of vaccine for elderlyNew development of vaccine for elderly

- immunomodulatory adjuvants- immunomodulatory adjuvants

- new antigen that readily ingest by APC- new antigen that readily ingest by APC

- live attenuate vaccine is not suitable- live attenuate vaccine is not suitable

- shortening interval of booster dose- shortening interval of booster dose

- repeated dose of booster vaccine- repeated dose of booster vaccine

1.121.12

Increase threshold to respond to danger signal

Functional defect of APC

Progressive loss of naïve T cell

Reduce naïve B cell isotype switching and Somatic Hypermutation

Increase effector T cell , restrict diversity of T cell

Aging of BM caused short duration of protection

Stratergies to reverse or delay Stratergies to reverse or delay immunosenescenceimmunosenescence

Thymic reconstructionThymic reconstruction Reduction of antigenic stimulationReduction of antigenic stimulation Depletion of senescent T cellsDepletion of senescent T cells

- KLRG-1,CD57 marker of sT cells- KLRG-1,CD57 marker of sT cells Caloric restrictionCaloric restriction

- data inconclusive- data inconclusive

MalnutritionMalnutrition Most common cause of SIDMost common cause of SID Primary and secondary malnutritionPrimary and secondary malnutrition PCM usually occur with micronutrient def.PCM usually occur with micronutrient def. Primary malnutritionPrimary malnutrition - atrophy of lymphoid organ- atrophy of lymphoid organ - T cell deficiency like CTA- T cell deficiency like CTA - barrier defect- barrier defect - activation of HPA axis - activation of HPA axis - Immunoglobulin ?- Immunoglobulin ? - decrease phagocytosis- decrease phagocytosis - reversible if renutrition- reversible if renutrition malnutritionmalnutrition ↔↔ infectioninfection

J Allergy Clin Immunol 2005 ;1151119-28J Allergy Clin Immunol 2005 ;1151119-28

Robert R Rich . Clinical immunology 3 rd edition

?

N=144

Micronutrient deficiencyMicronutrient deficiency

- Iron => cofactor in immune function- Iron => cofactor in immune function

- Zinc & copper => essential for thymic hormone,reduce - Zinc & copper => essential for thymic hormone,reduce

Th1 cytokineTh1 cytokine ,lymphopenia, reprogramming of immune,lymphopenia, reprogramming of immune

loss of NK, T cellsloss of NK, T cells

- Selenium => selenoprotein is antioxidant host defense - Selenium => selenoprotein is antioxidant host defense

systemsystem affecting lymphocyte and NK cellaffecting lymphocyte and NK cell

- antioxidant vitamin deficiency- antioxidant vitamin deficiency

1. vit A def. => panhypogrammaglob.impair mucosal 1. vit A def. => panhypogrammaglob.impair mucosal

barrier,NK ,PMN,Mbarrier,NK ,PMN,MǾ, impair Th1 and Th2Ǿ, impair Th1 and Th2

2. vit C def.=> regulator of redox and metabolic 2. vit C def.=> regulator of redox and metabolic

checkpoint and survival of immune systemcheckpoint and survival of immune system

3. vit E def.=> monocyte/M3. vit E def.=> monocyte/MǾ response, influence T cell Ǿ response, influence T cell

function by reduce PGE2 productionfunction by reduce PGE2 production

J Allergy Clin Immunol 2005 ;1151119-28J Allergy Clin Immunol 2005 ;1151119-28

J Allergy Clin Immunol 2005 ;1151119-28J Allergy Clin Immunol 2005 ;1151119-28

J Allergy Clin Immunol 2005 ;1151119-28J Allergy Clin Immunol 2005 ;1151119-28

N=265

Conclusion: CD4 T and B cell decrease in malnutrition with infectious pt.

Metabolic diseasesMetabolic diseases

Diabetes MellitusDiabetes MellitusUremiaUremia

Diabetes MellitusDiabetes Mellitus

Mortality rate 43% in ketosis with infectionMortality rate 43% in ketosis with infection 2/3 of bactermia in hospitalized pts. 2/3 of bactermia in hospitalized pts. Complexity of risk to infectionComplexity of risk to infection Immune defect in diabetes patientsImmune defect in diabetes patients - innate immunity- innate immunity - humoral innate immunity- humoral innate immunity - cellular innate immunity- cellular innate immunity - adaptive immunity- adaptive immunity

Humoral innate immunityHumoral innate immunity 1. complement function1. complement function - low C4 concentration but no play important - low C4 concentration but no play important role in infectionrole in infection 2. Cytokines2. Cytokines - low IL-1,IL-6 secretion after LPS - low IL-1,IL-6 secretion after LPS stimulationstimulation - advance glycocylated end product ?- advance glycocylated end product ? 3. Hyperglycemia/Glycosuria 3. Hyperglycemia/Glycosuria - enhance virulence of organism such as - enhance virulence of organism such as CandidaCandida - glucosuria enhance bacterial growth such as - glucosuria enhance bacterial growth such as E.coliE.coli

Defect in innate immunityDefect in innate immunity

Cellular innate immunityCellular innate immunity 1. Chemotaxis1. Chemotaxis - decrease Neu. Chemotaxis - decrease Neu. Chemotaxis - not depend on level of blood glucose - not depend on level of blood glucose 2. Adherence 2. Adherence - conflict data- conflict data 3. Phagocytosis3. Phagocytosis - inverse correlation with HbA1C- inverse correlation with HbA1C - improve phagocytosis if better control DM- improve phagocytosis if better control DM

4. Oxidative burst4. Oxidative burst

- lower in diabetic patients- lower in diabetic patients

- inconsistent data- inconsistent data

5. Killing5. Killing

- conflicting result - conflicting result

- Staph aureus killing is impaired all study- Staph aureus killing is impaired all study

but not in C. albicansbut not in C. albicans

Impair chemotaxis and phagocytosis in monocyteImpair chemotaxis and phagocytosis in monocyte

Adaptive immunityAdaptive immunity - CMI - CMI decrease lymphocyte prolipheration decrease lymphocyte prolipheration after stimulation, abnormal DTHafter stimulation, abnormal DTH - HMI- HMI normal level and function of Ignormal level and function of Ig normal response to vaccinenormal response to vaccine

UremiaUremia

Immune dysregulation in ESRD is complexImmune dysregulation in ESRD is complex metabolic acidosismetabolic acidosis ““Advanced oxidation protein product”Advanced oxidation protein product” Uremic toxin syndromeUremic toxin syndrome Impair immunity cuased by both low and high Impair immunity cuased by both low and high

molecular wt. toxinmolecular wt. toxin

Surgery and TraumaSurgery and Trauma

Disruption of epithelial barriers and cell Disruption of epithelial barriers and cell destructiondestruction

Excessive response of inflammationExcessive response of inflammation Nonspecific cell activation cause anergic Nonspecific cell activation cause anergic

immune stage to specific Agimmune stage to specific Ag Increase cortisol levelIncrease cortisol level

Robert R Rich . Clinical immunology 3 rd edition

splenectomysplenectomy Endothelial filtration organEndothelial filtration organ Phagocytosis,Opsonin ( IgM) ,complement Phagocytosis,Opsonin ( IgM) ,complement ( properdin)( properdin) OPSS - children > adultOPSS - children > adult -- highest risk in first 3yrshighest risk in first 3yrs - MCM organism =>streptococcus , - MCM organism =>streptococcus , H.influenza, staph. , capnocytophaga, H.influenza, staph. , capnocytophaga, intracellular organismintracellular organism - prevention 1. immunization- prevention 1. immunization 2. ATB prophylaxis2. ATB prophylaxis 3. education3. education

Environmental conditionEnvironmental condition UV lightUV light - induce T cell apoptosis,anergy- induce T cell apoptosis,anergy - poor Ag presentation- poor Ag presentation - nonspecific tolerogenic cytokines, Treg- nonspecific tolerogenic cytokines, Treg - humoral immunity and phagocyte relative - humoral immunity and phagocyte relative radioresistant but..radioresistant but.. Space flightSpace flight - weakening T ,NK cell immunity- weakening T ,NK cell immunity - increase release cortisol and suppressive - increase release cortisol and suppressive cytokinescytokines - concomittent with sleep disorder,radiation- concomittent with sleep disorder,radiation - not effect in humural immunity- not effect in humural immunity High altitudeHigh altitude - T and NK cell cytopenia- T and NK cell cytopenia - decrease serum IgG level- decrease serum IgG level

Robert R Rich . Clinical immunology 3 rd edition

conclusionconclusion

MCM cause of immune def. is malnutritionMCM cause of immune def. is malnutrition Extreme age and immune deficiencyExtreme age and immune deficiency Metabolic dis affect immune systemMetabolic dis affect immune system Surgical condition can effect immune Surgical condition can effect immune

systemsystem Environmental factor and immune defectEnvironmental factor and immune defect

Thank you for your Thank you for your attentionattention

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Nature Reviews Immunology 2008;8:685-98