Immunological Mechanisms Determining Why Some African Children Develop Severe Malarial Anaemia While

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Immunological Mechanisms Determining Why Some
African Children Develop Severe Malarial Anaemia
While Others Develop Cerebral Malaria in Response
to Infection with Plasmodium falciparum

• Wilson Mandala

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Fig 1 Prevalence and overlap for major clinical
syndromes of severe malaria

• Uncomplicated Malaria (UCM)

Severe Malarial Anaemia (SMA)
Cerebral Malaria (CM)
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Objectives

• SMA
• 1. Severe Pf malaria
  Why?
• CM
• 2. Hypotheses
• SMA immunonaivety and/or immunosuppression
• CM immunological priming and immunopathology.

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Plan of Investigation

• Leukocytes lymphocyte numbers and activation
  status
• a) in SMA, CM, UCM controls
• b) in acute and convalescence stages

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Role of Leukocytes Lymphocytes in Severe Malaria

• Leukocytes subsets
• Neutrophils
• Monocytes
• Lymphocyte Subsets
• T cells CD4 , CD8, Tregs
• NK, NKT gd T cells
• B cells

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Previous Studies

• T cells in acute UCM, CM SMA (Lars Hviid
  Infect Immunity 1997)-Ghanaian children
• gd ab T cells NK cells during infection
  (Rzepczyk C. M. Scand J Immunol. 1996) Australian
  Adults
• Neutrophilia in CM. (Amodu et al. Trop Med Hyg.
  1998) Nigerian children

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Patients, Materials Methods

• 6 months-5 years children at QECH with SMA, CM,
  UCM (Paeds. ward) controls (Surgical ward)
• BCS, MPS HCT used for grouping (Fig.2)
• FBC, IPT, HIV tests, blood cultures
• All HIV positive recruits excluded from analysis
• All MP positive controls excluded from analysis
• All with pathogenic organisms in blood cultures
  excluded from analysis.

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Fig 2 Criteria for determining eligibility for
each study group
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Results DiscussionsFig 3 Recruitment and
follow-up summary
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Fig 4 Distribution of age groups of children
recruited with CM SMA
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Fig 5 WBC, Neutrophils, Lymphocytes Monocytes
counts in controls and Malaria cases in acute
cases
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Fig 5 WBC, Neutrophils, Lymphocytes Monocytes
counts in controls and Malaria cases in acute
cases
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Fig 5 WBC, Neutrophils, Lymphocytes Monocytes
counts in controls and Malaria cases in acute
cases
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Fig 5 WBC, Neutrophils, Lymphocytes Monocytes
counts in controls and Malaria cases in acute
cases
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Fig 6 Absolute values of B, T cells, CD4 CD8
T cells in various malaria types in acute stages
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Fig 6 Absolute values of B, T cells, CD4 CD8
T cells in various malaria types in acute stages
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Fig 6 Absolute values of B, T cells, CD4 CD8
T cells in various malaria types in acute stages
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Fig 6 Absolute values of B, T cells, CD4 CD8
T cells in various malaria types in acute stages
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Fig 7 Absolute values of gd T, NK NKT in
various malaria types in acute stage
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Fig 7 Absolute values of gd T, NK NKT in
various malaria types in acute stage
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Fig 7 Absolute values of gd T, NK NKT in
various malaria types in acute stage
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Fig 8 WBC, Neutrophils, lymphocytes monocytes
values in acute convalescence stages in CM SMA
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Fig 8 WBC, Neutrophils, lymphocytes monocytes
values in acute convalescence stages in CM SMA
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Fig 8 WBC, Neutrophils, lymphocytes monocytes
values in acute convalescence stages in CM SMA
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Fig 8 WBC, Neutrophils, lymphocytes monocytes
values in acute convalescence stages in CM SMA
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Fig 9 Absolute values of lymphocyte subsets in
CM during acute convalescence stages
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Fig 9 Absolute values of lymphocyte subsets in
CM during acute convalescence stages
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Fig 10 Absolute values of lymphocyte subsets in
SMA during acute and convalescence stages
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Fig 10 Absolute values of lymphocyte subsets in
SMA during acute and convalescence stages
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Fig. 11 Activation levels for TCR ab T cells in
acute and convalescence stages in CM SMA
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Fig. 11 Activation levels for TCR ab T cells in
acute and convalescence stages in CM SMA
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Fig 12 Activation Levels in gd T cells in CM and
SMA in acute convalescence stages
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Fig 12 Activation Levels in gd T cells in CM and
SMA in acute convalescence stages
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Fig 13 Memory Naïve ratios for CD4T CD8T
cells in CM SMA in acute convalescence stages
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Fig 13 Memory Naïve ratios for CD4T CD8T
cells in CM SMA in acute convalescence stages
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Fig 14 T regulatory cells in CM and SMA during
acute and convalescence stages
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Fig 15 Summary of Results
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Limitations of the Study

• Normal TBNK phenotyping subsets vary with age.
  Age ranges for healthy Malawian children not
  available.
• Number of malaria episodes each children has had
  prior to recruitment
• Using peripheral blood - does not consider status
  in the secondary lymphoid tissues

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The Way forward

• Cytokine Analysis in serum
• Second Recruitment for intracellular cytokine
  staining Immunophenotyping.

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Acknowledgements

• Gates Malaria Partnership
• Dr. C. MacLennan and MSI Team
• Dr. Steve Ward
• Prof. M. E. Molyneux