ppt

1. Immunology and immunopathology
of
human parasitic infections

2. Microparasites and Macroparasites
• microparasites ?
• are small & multiply within their vertebrate host, often inside cells, thus
posing an immediate threat unless contained by an appropriate immune
response
• Macroparasites (i.e. helminths)
• are large and most do not multiply within their vertebrate host and,
therefore, do not present an immediate threat after initial infection
• immune response mounted is very different

3. Infection by protozoa & helminths
• long-lasting and, over a period of years
• inducing immunopathological changes
• may be more dangerous than infection itself

4. Infection by protozoa & helminths
• during the course of all infections, parasites die or are killed
• parasite molecules deposited on host cells may elicit autoimmune responses
• contribute to the pathology of infection

5. Infection by protozoa & helminths
• some parasites avoid eliciting an immune response
• by mimicking host molecules
• if effective- can be very successful
• if unsuccessful-can initiate an autoimmune reaction

6. Infection by protozoa & helminths
• majority of parasitic infections elicit powerful inflammatory
responses
• may alter, render nonfunctional or even destroy host tissues
• all parasitic infections are long-term and chronic
• there were no effective, protective immune responses

7. evidence for immunity is the rule
• majority of people experience clinical immunity
• prevalence of infection falls with age while immunological parameters
increase
• the uneasy compromise that exists after recovery can be broken
• by immunosuppressive drugs or concomitant infections
• immunity demonstrated every experimental model investigated

8. IMMUNITY TO PROTOZOA
Characteristics of protozoa in relation
to the immune response

9. Protozoal infections
• tend to be chronic
• associated with inappropriate immune responses
• immunodepression to superimposed infections
• immunopathological damage

10. long and chronic protozoal infections
• General pattern is:
• latent period
• during which few or no parasites can be detected
• a phase of logarithmic increase
• a crisis
• during which infection is brought under control
• a rapid or gradual decline
• leading to a chronic infection
• with the possibility of subsequent recrudescence's and long-term immuno-pathological
damage

11. All protozoal infections
• are accompanied by a number of immunological changes:
• production of specific antibodies
• usually IgM followed by IgG
• cell-mediated responses
• immunological responses have little or nothing to do with protection
• all protozoa are antigenically complex

12. T cell exhaustion in protozoan disease
• during acute infections
• host develops a successful T cell immune response
• characterized by:
• rapid proliferation
• robust poly functionality
• cytotoxicity
• production of IFN, TNF, and IL-2
• during chronic infection
• T cells become progressively exhausted
• gradually lose
• ability to mount an effective recall response to infection
• their poly functionality ability

13. T cell exhaustion in protozoan disease
• at first
• reduced IL-2 production and proliferative response are detected
• as exhaustion progress
• cells lose the ability to produce TNF
• finally, cells exhibiting the most severe phenotype
• are unable to secrete IFN in response to infection
• gradual upregulation of inhibitory receptors
• PD-1, LAG3, CD160, CTLA4, 2B4
• plays a central role in T cell exhaustion
• ultimately concomitant expression of multiple inhibitory receptors
• leads to severe T cell exhaustion

14. T cell exhaustion in protozoan disease
• exhausted T cells
• exhibit increased apoptosis potential
• leading to their complete deletion
• T cell exhaustion is highly dependent on:
• antigen load
• antigen burden

16. Immune response to protozoan parasites
and development of T cell exhaustion
• Protozoan parasites
• evoke a strong immune response
• begins with their encounter with a potent APCs [DCs]
• DC activation which is manifested by
• strong IL-12 production
• expression of multiple co-stimulatory molecules (CD80/86, CD40/40L, etc.)
• antigen is processed and presented to T cells in context of MHC molecules
• leading to their activation, clonal expansion, and differentiation into an
effector population

18. Parasite life cycle and consequences of T cell
exhaustion on disease
• infection with protozoan parasites T. gondii, Plasmodium sp., and
Leishmania sp.
• results in an intricate host–pathogen interaction
• the development of persistent disease as a consequence of T cell exhaustion
• factors leading to T cell exhaustion
• high levels of antigen
• inflammation (IL-12)
• immunoregulatory cytokines (IL-10)
• probably contribute to the sequelae associated with these infections

21. Diversity & dialogue in
immunity to helminths
Type 2 immunity

22. Type 2 immunity
• helminths do not replicate in the mammalian host
• infective stages must establish infection & then grow to sexual
maturity
• producing eggs or live offspring for transmission to next host

23. Type 2 immunity
• adult stages of these parasites can live for decades inured to
immune-mediated attack
• multicellular nature
• induce an entirely distinct immune response profile from microbial
pathogens

24. Type 2 immunity
• this canonical response is
• Th2 type
• involves cytokines IL-3, IL-4, IL-5, IL-9, IL-10 & IL-13
• antibody isotypes IgG1, IgG4 and IgE
• expanded populations of:
• eosinophils
• basophils
• mast cells
• alternatively activated macrophages

25. Type 2 immunity
• innate immune system
• anticipates and initiates the adaptive Th2 cell response
• continues to provide accompanying and mutually reinforcing pathways

26. Type 2 immunity
• central player in type 2 immunity is
• CD4+ Th2 cell
• expresses some or most of cytokines
• IL-13,4,5,9,10
• key chemokines
• CC-chemokine receptor 3 (CCR3) ligand
• CC-chemokine ligand 11 (CCL11; eotaxin 1)

27. Type 2 immunity
• central role of CD4+ Th2 cells include:
• Activation of the amplifiers & effector innate cells:
• Mast cells
• Basophils
• induction of smooth muscle type 2 response
• induction innate type to mucosal response
• induction innate type 2 tissue response
• induction of Humoral type 2 response
• it does that with help from amplifiers & effector innate cells (nuocyte, mast
cells, basophils ) & B cells

29. TH2-type effectors mechanisms in immunity
to helminthes
• mucosal immunity to helminths
• Th2-type responses are initiated and sustained by innate populations (epithelial
cell layer) through IL-25 & IL-33
• IL-13(Th2-type cytokines)
• increases cell turnover (resulting in ‘epithelial escalator’)
• induces differentiation of goblet cells
• produce mucins and anti-nematode protein resistin-like molecule-β (RELMβ)
• fluid transfer into gut is raised by action of mast cell proteases
• degrade tight junctions in epithelial cell layer
• adding to the ‘weep and sweep’ process
• Antibodies from B cells
• diminishing worm fitness and fecundity

31. Effector Th2 type immunity in peripheral tissue
• parasites are open to attack by full range of host innate effectors
• macrophages
• neutrophils
• Eosinophils
• Basophils
• platelets
• ability of these effector cells is often dependent on
• one or more isotypes of specific antibody
• often IgE, but IgM in the bloodstream
• complement
• armed granulocytes or macrophages can release damaging metabolic
ROI or RNI
• but in vivo killing methods are not yet fully understood

34. immunity in the repair of parasite-induced damage

35. Homeostasis and tolerance in helminth infections

36. Evolution of immune responsiveness to compensate for parasite immunosuppression

37. Immunity and
immunopathology to
viruses

38. Viral infections
• different viruses
•  clinical consequences
•  tissue damage
• reinfection = subclinical
• effective vaccines:
• measles, mumps, rubella, rotavirus & varicella zoster viruses

39. Tissue damage by immune system
• recruitment & activation of inflammatory cell types
• macro phages
• neutrophils
• cytotoxic cytokines?
• cationic proteins
• lipid mediators
• metalloproteinases
• oxygen burst
• ROS accumulated in mitochondria

40. Contribution by innate immune responses
• invading viruses & their replicative intermediates can be recognized
• TLRs 3,7,8,& 9
• endosomal
• viral NA & ds RNA intermediates
• NLR
• viral DNA genomes
• RIG-I
• viral genomic RNA or RNA encoded by genomic DNA
• activation of receptors
• production of pro-inflammatory cytokines and IFNs
• signals that recruit & activate cells involved in inflammation & induction of
adaptive immunity

41. Contribution by innate immune responses
• many viruses that persist trigger innate cells
• DCs
• NK
• macrophages
• to produce anti-inflammatory molecules:
• IL-10
• TGF-β

42. Immunity or immunopathology following viral
infection
• following entry into host cells
• viruses (non/cytopathic) replicate at site of infection
• Cytopathic viruses
• kill infected cells
• causing the release of cellular contents
• proteases and lysosomal enzymes
• digest extracellular matrix and create an inflammatory milieu
• neutrophils are rapidly recruited to site of infection
• release inflammatory mediators

43. Immunity or immunopathology following viral
infection
• innate cells recognize viral replication intermediates
• secrete pro-inflammatory cytokines
• helping to clear the virus
• contribute to tissue damage
• viral antigens are taken up by APC and carried to local draining
lymph nodes

44. Immunity or immunopathology following viral
infection
• depending on cytokine milieu created in draining LN
• different types of Th cell responses are induced
• primed CTLs migrate to site of infection
• kill virally infected cells
• thereby contributing to tissue damage
• Th cells migrating to site of infection
• contribute to tissue damage
• tissue damage is the main consequence of viral infection if
• control of aggressive Th cells & CTLs by TReg cells is impaired
• other inhibitory pathways fail to curtail them

45. Immunity or immunopathology following viral
infection
• Th cells also provide help to B cells to secrete antibodies
• form immune complexes that are deposited in certain tissues such as
• glomeruli of kidneys
• blood vessels
• cause immune complex-mediated disease

47. Inhibitory mechanisms to limit tissue damage
caused by T cells
• effector T cells upregulate inhibitory receptors such as
PD1: PDL1
T cell immunoglobulin domain and mucin domain protein 3(TIM3) : galectin 9
lymphocyte activation gene 3 (LAG3): MHC class II molecules
cytotoxic T lymphocyte antigen 4 (CTLA4): CD80 or CD86
• ligation of these receptors with their ligands delivers inhibitory signals to
the effector T cells
• controls their inflammatory activity & subsequent tissue damage

48. Inhibitory mechanisms to limit tissue damage
• production of produce anti-inflammatory cytokines by
• activated TReg
• specialized innate cells
• highly polarized effector T cells

50. Balance between pro-inflammatory and anti-inflammatory
mechanisms may decide the outcome of viral infection

51. Immunity to Fungal
Infections

55. Immunity against
Staphylococcus aureus
cutaneous infections