Zinc and Pneumonia

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Zincs Potential Role in

PneumoniaBy Siti Nashria Rusdhy


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Pneumonia

Pneumonia is the leading cause of death ofchildren under-5 worldwide

Responsible for an estimated19-29% of the 10million deaths in children under-5 worldwide

The fourth Millennium Development Goal: to reduce under-5 mortality two-thirds by 2015


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Zincs role in the body

Zinc is abundant in all cells of the human body Zinc is a vitalcomponent in about 300 enzymes

It is a cofactor in signalling pathways involvingzinc requiring proteins

It drives transcription factor activation andexpression


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Where can we get Zinc?

Animal products and sea foods constitute therichest sources of dietary zinc

BUTare expensive and inaccessible for many ofthe worlds poorest populations

Bioavailability of zinc from vegetable sources islow.

Thus, zinc deficiency is widespread in Asia andAfrica


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Zinc is beneficial in Diarrhea

Scientists first hit on zinc's effectiveness in the early1990s

Researchers from the Johns Hopkins School ofHygiene and Public Health gave children in New

Delhi a daily dose of syrup containing 20 mg ofzinc.

The rate of diarrhea dropped dramatically.

"Nobody believed the results."

"No one had an explanation why zinc worked."

http://www.time.com/time/magazine/article/0,9171,1914655,00.html#ixzz22yo1f9
http://www.time.com/time/magazine/article/0,9171,1914655,00.htmlhttp://www.time.com/time/magazine/article/0,9171,1914655,00.htmlhttp://www.time.com/time/magazine/article/0,9171,1914655,00.html


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WHAT ABOUT ZINCSROLE IN PNEUMONIA?


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Pneumonia

Up to half of pneumonia cases are caused by S.pneumoniae

S. pneumoniaeexpresseszincmetalloprotease B(ZmpB)induces TNF production in therespiratory tract promote inflammation.

Excessive immune reaction (due to effector cellsand the cytokines they secrete)inflammation-driven tissue damage.


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Potential role of Zinc in Pneumonia

Two distinctive potential roles for zinc in pneumonia :

1) preventive element when administered prior topneumonia disease;

2) zinc may change the course of prexisting pneumonia

when added as an adjunct to conventional antibiotictreatment potentially to reduce the severity andduration of pneumonia in sufferers.

Overall evidence (including pooled and metaanalyses)

zinc supplementation is beneficial for the prevention ofpneumonia disease in


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Animal models of Zinc deficiency

Young mice fed a zinc deficient diet for 28 days

rapidly thymic involution

Involuted thymi with decreased thymic weight andCellularity AND reduced T lymphocyte counts.

T cell numbers : thought to be due to a 60%increase in apoptosis of pre-T cells in the zincdeficient mice compared to the zinc replete controls.


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Human studies on Zinc deficiency

Zinc deficiency is associated with: atrophy of the thymus

lymphopenia

diminished cellular and antibody mediated responses

A study showed a 10 fold reduction in thymic sizeof malnourished children compared to controls.

Administration of an additional 2mg zinc per dayfurther1.5 fold increased thymus size

A smaller thymus was an independent andconsistent risk factor for mortality

Halving of thymus size was associated with a 70%increased mortality


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The Thymus

The human thymus is essential for the maturation ofT lymphocytes

T lymphocytes are a part ofthe adaptive immunityin humans

It reveals a relative increase for the first year oflife and plateaus until early adulthood, and thendeclines in size

Interestingly, serum zinc levels follow a similar

pattern in humans


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T cell maturation selection process

2 Selection Processes in the Thymus:

Positive selection:

permits the survival of only those T cells whose TCRs arecapable of recognizing foreign antigens presented on MHC

molecule.

Negative selection: eliminates T cells that react too

strongly with self-MHC plus self-peptide. (Self tolerance)

~98% of thymocytes die by apoptosis, it is expensivefor the host.

However, both processes are necessary toachieveMHC restriction and self-tolerance.


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Thymulin

A possible mediator of Zinc immunologicalproperties

Thymic epithelial cells (TECs) secrete inactivethymulin

Inactive thymulin binds zincactive thymulin binds high affinity receptors on T cells inducesfurther T cell receptor expressionT cell adhesion,migration and maturation

Thymulin has antiinflammatory properties

Reduced IL-6 levels were also seen in the lungs inthymulin or zinc administered rats comparedto controls

Zinc proinflammatory cytokines (TNF, IL6 and IL1)during lipopolysaccharide (LPS) stimulation


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In the intra-thymic compartment:

inactive thymulin generated by thymic epithelia + zinc

activeThymulin drives thymocyte development toexport mature T cells into the peripheral circulation

Zinc deficiency blocks intra-thymic T cell development

In the peripheral circulation: Zinc has the potential to drive further maturation,

activation and differentiation into helper (CD4),effectors and cytotoxic T lymphocytes (CTL)

possibly including naturally occurring regulatory T cells,which originate from the thymus.

Regulatory T cells may also produce TGFand IL10 tocounteract potential immune pathology.


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Two types of immunity

1. Innate (non-adaptive) first line of immune response relies on mechanisms that exist before infection

2. Acquired (adaptive) Second line of response (if innate fails)

relies on mechanisms that adapt after infection

handled by T- and B- lymphocytes one cell determines one antigenic determinant


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T LYMPHOCYTES AND CELL-

MEDIATED IMMUNITY

Originate from stem cells in bone marrowfollowed by migration to thymus gland

Maturation takes place in thymus gland followed

by migration to secondary lymphoid tissue

Respond to antigens on the surface of antigen

presenting cells (APCs)

Antigen presenting cells (APCs)

Macrophages Dendritic cells

B lymphocytes


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T LYMPHOCYTES AND CELL-

MEDIATED IMMUNITY

Antigen presenting cells (APCs) Ingest and process antigens then display fragments (short

peptides) on their surface in association with molecules of

major histocompatibility complex (MHC)

Major histocompatibility (MHC) molecules

MHC class I molecules

Present antigens to CD8 T cells

MHC class II molecules

Present antigens to CD4 T cells

T cells which encounter antigen differentiate into

effector T cells


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ROLES OF EFFECTOR T CELLS IN

IMMUNE RESPONSE

CD8 cytotoxic T cells Enter bloodstream and travel to infection site

Kill cells infected with viruses and other intracellular

microorganisms

CD4 TH1 helper T cells Enter blood stream and travel to infection site

Help activate macrophages

CD4 TH2 helper T cells

Work within secondary lymphoid tissues Help activate B cells


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Cell mediated immune response

Primary response production of specific clones of effector T cells and

memory clones

develops in several days

does not limit the infectionSecondary response

more pronounced, faster

more effective at limiting the infection

Example - cytotoxic reactions against intracellular parasites, delayedhypersensitivity (e.g., Tuberculin test) and allograft rejection


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Inflammatory Damage in pneumonia

Excess inflammation(by pro-inflammatory

cytokines, including TNF and IL-6)

immunopathologic lung damage in severepneumonia.

Regulatory T cells (Tregs) formed at the thymusplay a critical role in preventing immunopathologyresulting from exuberant and excessive inflammatory

responses to antigens in the host

It is predicted that:

Zinc deficiency affect thymusregulatory Tcell (Treg) numbers and function


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Zinc as an antioxidant

Zinc plays a part in the removal of ROS mayinduce apoptosis of host cells and tissues

ROS induce cell death through the Fas apoptosisreceptor in primary lung epithelial cells by the downregulation of apoptosis inhibitory proteins

Downregulation is reversed by the antioxidantscavenging enzymes glutathione peroxidase andSOD, for which zinc is a cofactor.

It is possible that in severe pneumoniadeath of

respiratory epithelial cells of the lung associated withincreased oxidative stress during this time, whichin the absence of zinc is exacerbated


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CONCLUSION

The balance of evidence suggests that zincsupplementation reduces the burden ofpneumonia in children under the age of 5 years,

But data is inconclusive and more studies are

required to establish its role as adjunctive therapy. Not surprisingly the existing evidence indicates that

a greater benefit from zinc may be expected if thesubjects are actually zinc deficient.


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References

Zinc Adjunct Therapy for Pneumonia The OpenImmunology Journal, 2011, Volume 4

http://www.bio.davidson.edu/courses/immunology/fla

sh/main.html

http://library.thinkquest.org/03oct/00520/lymphocytepdt.swf
http://www.bio.davidson.edu/courses/immunology/flash/main.htmlhttp://www.bio.davidson.edu/courses/immunology/flash/main.htmlhttp://www.bio.davidson.edu/courses/immunology/flash/main.htmlhttp://www.bio.davidson.edu/courses/immunology/flash/main.html


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THANK YOU


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Zinc deficiency

Causes a shift from the expected TH2 to a TH1 bias

Dominant pro-inflammatory cytokine profile whichhas been reported to exist potential to induceaccelerated proliferation (possibly driven by excess TH1cytokines, including IL-2) may lead to premature

senescence of T cells. Excess inflammation (driven by pro-inflammatory

cytokines, including TNF and IL-6) could contribute toimmunopathologic lung damage in severe pneumonia.

A balanced cytokine profile may counter disruptions of

the TH1/TH2 balance and the effects of proinflammatorycytokines during zinc adequacydampening/alleviating potential lung injury associatedwith pneumonia disease.


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Two types of immunity

1. Innate (non-adaptive) first line of immune response relies on mechanisms that exist before infection

2. Acquired (adaptive) Second line of response (if innate fails)

relies on mechanisms that adapt after infection

handled by T- and B- lymphocytes one cell determines one antigenic determinant


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Innate immunity: mechanisms

Mechanical barriers / surface secretion

skin, acidic pH in stomach, cilia

Humoral mechanisms

lysozymes, basic proteins, complement, interferons

Cellular defense mechanisms natural killer cells neutrophils, macrophages, mast cells,

basophils, eosinophils

NeutrophilNK Cell MonocyteMacrophageBasophils &Mast cells

Eosinophils

d i i i


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Adaptive immunity:

second line of response

Based upon resistance acquired during life

Relies on genetic events and cellular growth

Responds more slowly, over few days

Is specific each cell responds to a single epitope on an antigen

Has anamnestic memory

repeated exposure leads to faster, stronger response

Leads to clonal expansion


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Adaptive Immunity: active and passive

Active Immunity Passive Immunity

Natural clinical, sub-clinicalinfection

via breast milk,

placenta

Artificial Vaccination:

Live, killed, purified

antigen vaccine

immune serum,

immune cells


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Adaptive immunity: mechanisms

Cell-mediated immune response (CMIR)

T-lymphocytes

eliminate intracellular microbes that survive within

phagocytes or other infected cells

Humoral immune response (HIR)

B-lymphocytes

mediated by antibodies

eliminate extra-cellular

microbes and their toxins

Plasma cell(Derived from B-lymphocyte,

produces antibodies)


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Cell-mediated immune response

1.

T-cell recognizes peptide

antigen on macrophage

in association with major

histo-compatibility

complex (MHC) class identifies molecules on

cell surfaces

helps body distinguish

self from non-self

2. T-cell goes into effectors

cells stage that is able to kill

infected cells


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T lymphocytes

2 types

helper T- lymphocytes (CD4+)

CD4+ T cells activate phagocytes to kill microbes

cytolytic T-lymphocyte (CD8+) CD8+ T cells destroy infected cells containing microbes

or microbial proteins


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Cell mediated immune response

Primary response production of specific clones of effector T cells and

memory clones

develops in several days

does not limit the infectionSecondary response

more pronounced, faster

more effective at limiting the infection

Example - cytotoxic reactions against intracellular parasites, delayedhypersensitivity (e.g., Tuberculin test) and allograft rejection


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Humoralimmune response1. B lymphocytes recognize

specific antigens

proliferate and

differentiate into

antibody-secreting

plasma cells2. Antibodies bind to specific

antigens on microbes;

destroy microbes via

specific mechanisms

3. Some B lymphocytes

evolve into the resting state

- memory cells


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Antibodies (immunoglobulins)

Belong to the gamma-globulin fraction ofserum proteins

Y-shaped or T-shaped polypeptides

2 identical heavy chains

2 identical light chains

All immunoglobulins are not antibodies

Five kinds of antibodies

IgG, IgM, IgA, IgD, IgE


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Zinc and Pneumonia

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