An Overview to Innate immunity for students of Medical Sciences

1. Innate Immunity
by
Getso, Muhammad Ibrahim
Microbiology Dept; SRM MCH & RC

2. Synopsis
• Introduction
• Properties of innate immunity
• Components of innate immunity
– Epithelial barriers
– Cellular mechanisms
– Humoral mechanisms
• Role of innate immunity in stimulating adaptive
immune response
• Defects in innate immunity
• Current issues in innate immunity

3. Introduction
• The term immunity, microbiologically, refers to
state of relative resistance of host to
infectious agents (microbes and their
products).
• The hosts’ defense against microbial infections
is fundamentally the function of two major
types of immune system; Innate Immune
System and Adaptive Immune System.
• Innate forms the first line of defense;
is phylogenetically older;
non specific;
Immediate and rapid;
needs not prior exposure;
not associated with memory

5. Principle mechanisms of
Innate and Adaptive Immunity

6. Innate Immunity
•E.g; Animals are resistant to plant pathogens.
•syphilis, gonorrhea, measles, polio affect only humans not lower
animals
Species
Resistance
•Eg; Algerian sheeps are resistant to anthrax
•African natives with HbAS are resistant to P. falciparum
Racial
resistance
•Affected by factors such as Age, Sex, Stress, Malnutrition,
Comorbidity or other Therapy
Individual
resistance
- Innate immunity is constitutive and can be
considered at Species, Racial and Individual level.

7. Components of innate immunity
Humoral:
-Interferons
-Chemokines
-complements
Cellular:
-Granulocytes
-Agranulocytes
Epithelial:
-physical barrier
-chemical barrier
-biological barrier

8. Cellular components of innate
immunity
NK Cells
Recognize
and destroy
cancer and
virally
infected
cells

9. Cellular defense mechanism of
innate immunity
• Recognition via receptors:
o Pattern Recognition Receptors (PRRs)
o Toll-like Receptors (TLRs)
o Killer Activation Receptors (KARs)
o Killer Inhibtion Receptors (KIRs)
o Complement Receptors (CRs)
o Fc Receptors (FcRs)
• Response via
o Phagocytosis
o Inflammation

10. Pathogen Associated Molecular patterns (PAMPs)
Structures common for certain groups/classes of pathogens
- essential for their life, replication and/or infectivity
structures of bacterial cell wall (LPS, peptidoglycan, flagellin, Capular...)
nucleic acids of pathogens (dsRNA, unmethylated CpG dinucleotides...)
- not present on human cells
Examples:
Lipoproteins
Flagellin
Capsular antg

11. Toll-like Receptors

12. Toll-like Receptors
• Transmemebrane molecules as receptors to
recognize microbial components
• They’re homologous to Drosophila protein, Toll.
• About 10-12 different TLR identified based on
sequence homology to Drosophila Toll.
• They are named as TLR-1, TLR-2, TLR-3…….
• Functions depend on the molecule identified
• Binding to ligand initiates signaling pathways leading
to activation of transcription factors that switch on
cytokine genes.

13. Mechanism of Killer Activation Killer Inhibtion Receptors

14. Recognition and Response by Macrophages

15. Role of phagocytes in innate immunity
Order of events in infection
1. Entry of pathogen
2. Recognition of pathogen
3. Phagocytosis and killing of a pathogen (macrophages)
- reactive oxygen species (ROS), nitric oxide (NO)
and lysosomal enzymes

16. Phagocytosis and
killing of
microbes
Pathogen recognition

17. Zipping of membrane
around microbe
Phagocytosis and
killing of
microbes

18. Ingestion of microbe
Phagocytosis and
killing of
microbes

19. Fusion of phagosome
with lysosome
Phagocytosis and
killing of
microbes

20. Phagocyte activation
Phagocytosis and
killing of
microbes

21. Killing of
microbe
Phagocytosis and
killing of
microbes
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22. Role of phagocytes in innate immunity
Order of events in infection
1. Entry of pathogen
2. Recognition of pathogen
3. Phagocytosis and killing of a pathogen
4. Induction of inflammation (macrophages)
- production of pro-inflammatory cytokines (TNF, IL-1, chemokines...)

23. Inflammation induction
Proinflammatory cytokines
TNF ― Tumor Necrosis Factor
IL-1 ― Interleukin-1
Chemokines ― Chemotactic cytokines

24. Role of phagocytes in innate immunity
Order of events in infection
1. Entry of pathogen
2. Recognition of pathogen
3. Phagocytosis and killing of a pathogen
4. Inflammation induction
5. Attraction of cells to infection site
- adhesive molecules (selectins and integrins) and chemokines

25. Leukocytes arrive at the site of infection (extravasation)
Weak binding
and rolling Activation and
firm binding
Endothelium
TNF & IL-1
Transmigration
Arrival to the site of infection
Selectins Integrins
Various adhesive
molecules
ChemokinesMacrophages

26. Role of phagocytes in innate immunity
Order of events in infection
1. Entry of pathogen
2. Recognition of pathogen
3. Phagocytosis and killing of a pathogen
4. Inflammation induction
5. Attraction of cells to infection site
6. Pathogen elimination and/or adaptive immunity activation
(dendritic cells)
- cytokines, costimulatory molecules...

27. Role of phagocytes in innate immunity
Order of events in infection
1. Entry of pathogen
2. Recognition of pathogen
3. Phagocytosis and killing of a pathogen
4. Inflammation induction
5. Attraction of cells to infection site
6. Pathogen elimination and/or adaptive immunity activation
7. Tissue repair and remodeling (macrophages)
- enzymes and cytokines (growth factors, metaloproteinases...)

28. Mechanism of phagocytosis

29. Role of NK cells in innate immunity
Killing of cells infected by
intracellular pathogens
(eg. viruses) and
tumor cells
Activation of
macrophages (by IFN-γ)

30. Humoral components of Innate Immunity

31. Properdin

32. Components of complement system

34. Defects in innate immune system
• Cystic fibrosis- gene defect in ion-gated chloride channel, leading to
accumulation of abnormally thick secretion in air ways.
• Congenital achlorhydria- inability of gastric mucosal cell to produce HCl,
• Chronic Granulomatous Disease- congenital defect in NADP phargosome
oxidase (NADP phox) production, leading to poor generation of ROSs and RNS by
phagocytes.
• Congenital deficiency of C8 Compliment- Defective MAC formation
• Hereditary angioedema (C1 esterase deficiency)-excessive C1s activity
• Factor I deficiency- uncontrolled complement activation, leading to complement
protein depletion.

35. Evaluation of innate immunity
• Single, specific and direct lab test is not available in practice
• Inferences can be drawn from level of certain components that can
be evaluated in the labs. Examples:
• Evaluation of phagocyte defects by
- Neutrophil Oxidative Burst using Nitro Blue-Tetrazolium (NBT) test
- Dihydrorhodamin (DHR) flow cytometry
-Neutrophil enzyme assay (G6PD, Myeloperoxidase…..)
• Specific complement components assay (Eg CH50 ,C1q, C2)

36. Role of innate immunity in stimulation of adaptive immune response
T or B-cells need two signals for activation
First signal: antigen recognition while Second signal: derrived by innate immunity
Lymphocyte proliferation and
differentiation

37. Current Issues in Innate Immunity
• Application of innate immune system in:
• Pathogenesis of disesease
i. Role of TLR 7 and 9 in pathogenesis of AIDs (Arthritis
Foundation research 2007, USA.)
ii. Association between Acute Coronary Syndrome and
elevated level of MBL (Kardiologiia Jounal 2014, 54(1):27-33)
iii. Association btw TLR 2 gene variants and Early Onset
Bipolar disorder. (Jose Olivera et al; J Affective Dis (May 2014)
vol 165, pg 135-141)

38. • Disease Diagnosis:
i. Use of TNF-α and IL-1β as markers and prognostic
factors in sepsis and septic shock. (Jacob RF and Tabor DR, 1990.)
ii. Use of lipocarlin-2 to differentiate between acute
bacterial and acute viral infection. (Xu et, 1995.)
iii. Use of Neutophil Gelatinase Associated Lipocarlin
(NGAL) to descriminate between Acute Bact Meningitis
and Acute Viral Meningitis in patient with clinical
Meningitis symptoms.(Guiddir T et al, May 2014)

39. • Disease Therapy:
i. Use of INF-α in HCV infection treatment
ii. Use of IL-13-PE (IL-13 immunotoxin) for
treatment of Pancreatic Adenocarcinoma
(Toshio F et al; Int J Cancer (2011):28; 12211-1231)
iii. Use of aerosolized IL-2 for treatment of
pulmonary metastatic liver cancer (2014,
ongoing research in US National Inst of Health
Development; Clinicaltrial.gov)

40. References
• Abbas AK, Litchman AH (2004). Basic Immunology 2nd Ed. Saunders (Elsevier Inc.) USA
• Baron S. (1996). Medical Microbiology, 4th Ed. The University of Texas Medical Branch at Galveston
( Online textbook) Ch.86-92
• Christine DS (2010). Clinical immunology and serology : a laboratory perspective, 3rd Ed. FA Davis
Company, Philadelphia, USA.
• John BZ (2009). Essential Clinical Immunology, 2nd Ed. Cambridge University Press, UK.
• Johnson AG, Ziegler R J, Lukasewycz O A, Hawley L B; (2002). BRS Microbiology and Immunology,
4th Edition. Lippincott Williams & Wilkins. USA
• Owen JA, Punt J, Stranford SA (2013). KUBY Immunology 7th Ed. W. H. Freeman and Company, NY.
USA
• Paul WE (2003). Fundamental Immunology 5th ed. Lippincott Williams & Wilkins Publishers, USA.
Ch 17.
• Warren Levinson (2010). Review of Medical Microbiology & Immunology 5th Ed. McGraw-Hill
Companies, Inc. USA.