Zincs Potential Role in Pneumonia

By Siti Nashria Rusdhy

Pneumonia

Pneumonia is the leading cause of death of children under-5 worldwide Responsible for an estimated19-29% of the 10 million deaths in children under-5 worldwide The fourth Millennium Development Goal:

to reduce under-5 mortality two-thirds by 2015

Zincs role in the body

Zinc is abundant in all cells of the human body Zinc is a vital component in about 300 enzymes It is a cofactor in signalling pathways involving zinc requiring proteins It drives transcription factor activation and expression

Where can we get Zinc?

Animal products and sea foods constitute the richest sources of dietary zinc BUT are expensive and inaccessible for many of the worlds poorest populations Bioavailability of zinc from vegetable sources is low. Thus, zinc deficiency is widespread in Asia and Africa

Zinc is beneficial in Diarrhea

Scientists first hit on zinc's effectiveness in the early 1990s Researchers from the Johns Hopkins School of Hygiene and Public Health gave children in New Delhi a daily dose of syrup containing 20 mg of zinc. 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

WHAT ABOUT ZINCS ROLE IN PNEUMONIA?

Pneumonia

Up to half of pneumonia cases are caused by S. pneumoniae S. pneumoniae expresses zinc metalloprotease B (ZmpB) induces TNF production in the respiratory tract promote inflammation. Excessive immune reaction (due to effector cells and the cytokines they secrete) inflammationdriven tissue damage.

Potential role of Zinc in Pneumonia

Two distinctive potential roles for zinc in pneumonia :

1) preventive element when administered prior to pneumonia disease; 2) zinc may change the course of prexisting pneumonia when added as an adjunct to conventional antibiotic treatment potentially to reduce the severity and duration of pneumonia in sufferers.
Overall evidence (including pooled and metaanalyses) zinc supplementation is beneficial for the prevention of pneumonia disease in <5 year olds

Animal models of Zinc deficiency

Young mice fed a zinc deficient diet for 28 days rapidly thymic involution Involuted thymi with decreased thymic weight and Cellularity AND reduced T lymphocyte counts. T cell numbers : thought to be due to a 60% increase in apoptosis of pre-T cells in the zinc deficient mice compared to the zinc replete controls.

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 size of malnourished children compared to controls. Administration of an additional 2mg zinc per day further 1.5 fold increased thymus size A smaller thymus was an independent and consistent risk factor for mortality Halving of thymus size was associated with a 70% increased mortality

The Thymus

The human thymus is essential for the maturation of T lymphocytes T lymphocytes are a part of the adaptive immunity in humans It reveals a relative increase for the first year of life and plateaus until early adulthood, and then declines in size Interestingly, serum zinc levels follow a similar pattern in humans

T cell maturation selection process

2 Selection Processes in the Thymus: Positive selection:

permits the survival of only those T cells whose TCRs are capable 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 expensive for the host. However, both processes are necessary to achieve MHC restriction and self-tolerance.

Thymulin

A possible mediator of Zinc immunological properties Thymic epithelial cells (TECs) secrete inactive thymulin Inactive thymulin binds zinc active thymulin binds high affinity receptors on T cells induces further T cell receptor expression T cell adhesion, migration and maturation Thymulin has antiinflammatory properties Reduced IL-6 levels were also seen in the lungs in thymulin or zinc administered rats compared

to controls

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

In the intra-thymic compartment: inactive thymulin generated by thymic epithelia + zinc activeThymulin drives thymocyte development to export 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 TGF and IL10 to counteract potential immune pathology.

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

T LYMPHOCYTES AND CELLMEDIATED IMMUNITY

Originate from stem cells in bone marrow followed 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

T LYMPHOCYTES AND CELLMEDIATED 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) MHC class I molecules

Major histocompatibility (MHC) molecules

Present antigens to CD8 T cells Present antigens to CD4 T cells

MHC class II molecules

T cells which encounter antigen differentiate into effector T cells

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 Enter blood stream and travel to infection site Help activate macrophages Work within secondary lymphoid tissues Help activate B cells

CD4 TH1 helper T cells

CD4 TH2 helper T cells

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 infection

Secondary response
more pronounced, faster more effective at limiting the infection Example - cytotoxic reactions against intracellular parasites, delayed hypersensitivity (e.g., Tuberculin test) and allograft rejection

Inflammatory Damage in pneumonia

Excess inflammation (by pro-inflammatory cytokines, including TNF and IL-6) immunopathologic lung damage in severe pneumonia. Regulatory T cells (Tregs) formed at the thymus play a critical role in preventing immunopathology resulting from exuberant and excessive inflammatory responses to antigens in the host

It is predicted that: Zinc deficiency affect thymus regulatory T cell (Treg) numbers and function

Zinc as an antioxidant

Zinc plays a part in the removal of ROS may induce apoptosis of host cells and tissues ROS induce cell death through the Fas apoptosis receptor in primary lung epithelial cells by the down regulation of apoptosis inhibitory proteins Downregulation is reversed by the antioxidant scavenging enzymes glutathione peroxidase and SOD, for which zinc is a cofactor. It is possible that in severe pneumonia death of respiratory epithelial cells of the lung associated with increased oxidative stress during this time, which in the absence of zinc is exacerbated

CONCLUSION

The balance of evidence suggests that zinc supplementation reduces the burden of pneumonia 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 the subjects are actually zinc deficient.

References

Zinc Adjunct Therapy for Pneumonia The Open Immunology Journal, 2011, Volume 4 http://www.bio.davidson.edu/courses/immunology/fla sh/main.html http://library.thinkquest.org/03oct/00520/lymphocytep dt.swf

THANK YOU

Zinc deficiency

Causes a shift from the expected TH2 to a TH1 bias Dominant pro-inflammatory cytokine profile which has been reported to exist potential to induce accelerated proliferation (possibly driven by excess TH1 cytokines, 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 to immunopathologic lung damage in severe pneumonia. A balanced cytokine profile may counter disruptions of the TH1/TH2 balance and the effects of proinflammatory cytokines during zinc adequacy dampening/alleviating potential lung injury associated with pneumonia disease.

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

Innate immunity: mechanisms

Mechanical barriers / surface secretion

skin, acidic pH in stomach, cilia

lysozymes, basic proteins, complement, interferons natural killer cells neutrophils, macrophages, mast cells, basophils, eosinophils

Humoral mechanisms

Cellular defense mechanisms

NK Cell

Eosinophils

Neutrophil

Basophils & Mast cells

Monocyte Macrophage

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

Adaptive Immunity: active and passive

Active Immunity Natural clinical, sub-clinical infection Passive Immunity via breast milk, placenta

Artificial

Vaccination:
Live, killed, purified antigen vaccine

immune serum, immune cells

Adaptive immunity: mechanisms

Cell-mediated immune response (CMIR)

T-lymphocytes eliminate intracellular microbes that survive within phagocytes or other infected cells
B-lymphocytes mediated by antibodies eliminate extra-cellular microbes and their toxins
Plasma cell (Derived from B-lymphocyte, produces antibodies)

Humoral immune response (HIR)

Cell-mediated immune response

1.

2.

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 T-cell goes into effectors cells stage that is able to kill infected cells

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

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 infection

Secondary response
more pronounced, faster more effective at limiting the infection Example - cytotoxic reactions against intracellular parasites, delayed hypersensitivity (e.g., Tuberculin test) and allograft rejection

Humoral immune response

1.

2.

3.

B lymphocytes recognize specific antigens proliferate and differentiate into antibody-secreting plasma cells Antibodies bind to specific antigens on microbes; destroy microbes via specific mechanisms Some B lymphocytes evolve into the resting state - memory cells

Antibodies (immunoglobulins)
Belong

to the gamma-globulin fraction of serum 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