INNATE IMMUNITY

IMMUNITY (Protection)

Innate
Available at birth
Protects newborn

Adaptive
Acquired
Consequence of exposure to foreign substance
 Body Defenses Against Invasion

INNATE IMMUNITY ACQUIRED IMMUNITY

Rapid responses to a Slower responses to
broad range of microbes specific microbes

External defenses Internal defenses

(1st line of defense) (3rd line of defense)
(2nd line of defense)
Skin Phagocytic cells Humoral response
Mucous membranes Antimicrobial proteins (antibodies)
Secretions Inflammatory response
Invading
Cell-mediated response
microbes Natural killer cells
(cytotoxic
(pathogens)
lymphocytes)
MECHANISMS
Extracellular microbes

Intracellular pathogens

Pattern recognition

Expressed within minutes to hours

Effectors – phagocytosis
inflammation

COMPONENTS

Phagocytes – neutrophils, macrophages

Complement

Fibrinolytic system

Vascular endothelium

Cytokines and chemokines

FIRST LINE OF DEFENSE

Physical and chemical barriers

Epithelium
Mucocilliary movement
Low pH and high fatty acid
Mucin
Iron-binding proteins
Lactoferrin (extrcellular space)
Nramp 1 gene- host can acquire Fe2+ to generate ROS
Nramp 2 gene depletes Fe2+ from phagosome

Normal flora – biological barrier

THE INNATE IMMUNE RESPONSE

Pathogen-associated molecular patterns (PAMP)

Host cell receptors that recognize PAMP

Encoded within germline
Phylogenetically conserved

Toll-like receptors
Mannose-binding lectin
Lysozyme – degrades peptidoglycan

Effectors
Granulocytes
• Contain cytoplasmic graduals

• Divided into three types

• Neutrophils
• Basophils
• Eosinophils
PHAGOCYTES

Activated by PAMP

Mannose receptors

Scavenger receptors

Toll-like receptors

Chemotactic receptors

Opsonic receptors

Phagolysosomes – hydrolytic enzymes

Defensins and cathelicidins

Respiratory burst
 Phagocytosis
Processes of
phagocytosis
Chemotaxis

Recognition/attachment

Engulfment

Phagosome lysosome
Destruction and digestion
fusion
• Organism killed due to
lack of oxygen and
decreased pH

Exocytosis
• to external environment
OTHER EFFECTORS

Epithelial cells – defensins

Intraepithelial T lymphocytes

Natural killer cells (NK cells)

Natural killer T (NKT) cells – recognize glycolipids

 Model of Immune Response to Inhaled Aspergillus Species

Segal B. N Engl J Med 2009;360:1870-1884

The Signaling Pathway of Toll-like Receptors

Medzhitov R and Janeway C. N Engl J Med 2000;343:338-344

TOLL - LIKE RECEPTORS
 Toll-like Receptor 4 (TLR4)

Kiechl, S. et. al. N Engl J Med 2002;347:185-192

 The Cryopyrin Inflammasome

Drenth J and van der Meer J. N Engl J Med 2006;355:730-732

Group 2 – Complement System
The Lectin Pathway of Complement Activation

Medzhitov R and Janeway C. N Engl J Med 2000;343:338-344

Membrane Attack Complex
 Fig. 1. Pathway of fever development in response to infection, inflammation, or trauma

Leon, L. R. J Appl Physiol 92: 2648-2655 2002;

doi:10.1152/japplphysiol.01005.2001

Copyright ©2002 American Physiological Society

 Inflammation
Inflammation occurs in
response to tissue damage

Four cardinal signs

• Heat
• Pain
• Redness
• Swelling
 The Acute Inflammatory Response

Delves P and Roitt I. N Engl J Med 2000;343:37-49

Icam-1
 Janeway, Charles A., Jr. (2001) Proc. Natl. Acad. Sci. USA 98, 7461-7468

Copyright ©2001 by the National Academy of Sciences

 A New Type of Immune Cell

Smyth M. N Engl J Med 2006;354:2282-2284

 Early Biochemical Events in Sepsis

Wheeler, A. P. et. al. N Engl J Med 1999;340:207-214

The Normal Alveolus (Left-Hand Side) and the Injured Alveolus in the Acute Phase of Acute Lung
Injury and the Acute Respiratory Distress Syndrome (Right-Hand Side)

Ware L and Matthay M. N Engl J Med 2000;342:1334-1349

SWITCHING OFF THE INNATE SYSTEM
SWITCHING OFF THE INNATE SYSTEM

NKT – CELLS

CD4+ REGULATORY CELLS

INTERLEUKIN-10

TGF-beta
The Actions of Interleukin-1 (IL-1) and Interleukin-1-Receptor Antagonist (IL-1Ra)

Dinarello C. N Engl J Med 2000;343:732-734

DISORDERS OF THE INNATE RESPONSE

Chronic granulomatous disease (CGD)

Mutations in the respiratory burst oxidase (NADPH oxidase)

Defective IFN-gamma receptor function

Mycobacteriosis
Salmonellosis
Listeriosis

Disorders of the complement system

Excessive danger signalling

Sepsis
Cryopyrin disorders
Activation of innate immunity system during aging :
NF-kB signaling is
the molecular culprit of inflamm-aging.

Ageing Res Rev.  2008; 7(2):83-105 (ISSN: 1568-1637)

Clinical Features of Chronic Granulomatous Disease

Lekstrom-Himes J and Gallin J. N Engl J Med 2000;343:1703-1714

Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic
Granulomatous Disease

Lekstrom-Himes J and Gallin J. N Engl J Med 2000;343:1703-1714

NADPH OXIDASE NBT TEST
Diagnosis of Phagocytic Defect on the Basis of Light-Microscopical Findings

Lekstrom-Himes J and Gallin J. N Engl J Med 2000;343:1703-1714

 LEUKOCYTE ADHAESION DEFICIENCY

WBC 72 000 / ul

A very high WBC count is characteristic of LAD !

Delayed separation of the umbilical cord (poor wound healing)

Essential Molecular Players in the Multistep Adhesion Cascade

von Andrian, U. H. et. al. N Engl J Med 2000;343:1020-1034

 FIG. 8. Gi family G proteins are centrally involved in neutrophil migration and activation
and mediate their effects via the {beta}2- and {beta}3-isoforms of phospholipase C (PLC-
{beta}2/{beta}3), phosphoinositide 3-kinases (PI-3-K), or the RacGEF P-Rex1

Wettschureck, N. et al. Physiol. Rev. 85: 1159-1204 2005;

doi:10.1152/physrev.00003.2005

Copyright ©2005 American Physiological Society

 Interferon-{gamma}-Interleukin-12 Signal-Transduction Cascade

Lekstrom-Himes J and Gallin J. N Engl J Med 2000;343:1703-1714

IL-12 SIGNALLING
HEREDITARY PERIODIC-FEVER SYNDROMES
Hereditary Systemic Autoinflammatory Disorders
Familial cold autoinflammatory syndrome

Muckle-Wells syndrome

Episodes of urticarial rash and systemic inflammation

No bony overgrowth
No CNS abnormalities

Mutations in CIAS1 gene – encodes cryopyrin (NALP3)

CIAS1-associated diseases
FCAS MWS
Serial Measurements of Plasma Concentrations of Serum Amyloid A Protein in Two Patients with
the Muckle -Wells Syndrome

Hawkins P et al. N Engl J Med 2003;348:2583-2584

Neonatal-onset multisystem inflammatory disease (NOMID)
Chronic infantile neurologic, cutaneous, articular syndrome
(CINCA)

Urticaria-like rash in 1st 6 weeks of life

Bony overgrowth in knees
Chronic aseptic meningitis
Increased intracranial pressure
Cerebral atrophy
Ventriculomegaly
Chronic papilledema
Optic nerve atrophy with loss of vision
Mental retardation
Seizures
Sensorineural hearing loss
Short stature
Hepatosplenomegaly
Leukocytosis
Increased serum amyloid A, CRP and ESR
20 % mortality before adulthood
Systemic amyloidosis in 25 % cases
Goldbach-Mansky R et al. N Engl J Med 2006, 355: 583-592
Inflammatory Organ Manifestations in Neonatal-Onset Multisystem Inflammatory Disease before
(Panels A, C, E, and G) and after (Panels B, D, F, and H) Treatment with Anakinra

Goldbach-Mansky R et al. N Engl J Med 2006;355:581-592

Glomerular Amyloid Deposition in a Renal-Biopsy Specimen (Congo Red, x400)

Hull K et al. N Engl J Med 2002;346:1415-1416

 The Cryopyrin Inflammasome

Drenth J and van der Meer J. N Engl J Med 2006;355:730-732

 Fig. 2. Summary of fever data obtained with gene knockout mice

Leon, L. R. J Appl Physiol 92: 2648-2655 2002;

doi:10.1152/japplphysiol.01005.2001

Copyright ©2002 American Physiological Society

Mean ({+/-}SE) Maximal Changes in Body Temperature, Pulse Rate, and Systolic Blood Pressure
during and after the Jarisch-Herxheimer Reaction in Control Patients and Those Treated with
Anti-TNF-{alpha} Fab

Fekade D et al. N Engl J Med 1996;335:311-315

 INTERLEUKIN-1b

COX-2 PGE-2
INTERLEUKIN-6

INTERLEUKIN-18

CHEMOKINES NEUTROPHILS
MONOCYTES
Table 1 Auto-inflammatory Diseases

Familial Mediterranean Fever (FMF)

Familial Cold Auto-inflammatory Syndrome (FCAS)

Muckle-Wells Syndrome (MWS)

Neonatal Onset Multi-System Inflammatory Disease

(NOMID)

Hyper IgD Syndrome

Adult Onset Still's Disease

Systemic Onset Juvenile Idiopathic Arthritis

Schnitzler's Syndrome

Anti-Synthetase Syndrome

TNF Receptor-Associated Periodic Syndrome

Macrophage Activation Syndrome

Normocomplementemic Urticarial Vasculitis

Pericarditis in Adult Still's Disease

Behçet's Syndrome

PAPA Syndrome

Blau's Syndrome

Sweet's Syndrome

Urate Crystal Arthritis (Gout)

Type 2 Diabetes
 Distinctive Features of Familial Mediterranean Fever, the Hyper-IgD Syndrome, and the Tumor
Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome

Drenth J and van der Meer J. N Engl J Med 2001;345:1748-1757

 Structure of the Gene for Familial Mediterranean Fever (MEFV )

Drenth J and van der Meer J. N Engl J Med 2001;345:1748-1757

Hypothesized Pathogenesis of the Tumor Necrosis Factor (TNF) Receptor-Associated Periodic
Syndrome

Drenth J and van der Meer J. N Engl J Med 2001;345:1748-1757

Petechiae and Purpura on the Lower Right Leg during a Febrile Attack in a Patient with the
Hyper-IgD Syndrome

Drenth J and van der Meer J. N Engl J Med 2001;345:1748-1757

 FigCEREBELLAR
1. MRI of patientATROPHY – 6HYPER IgD syndrome
3 at the age of years, showing the severe cerebellar atrophy

Prietsch, V. et al. Pediatrics 2003;111:258-261

Copyright ©2003 American Academy of Pediatrics

 Pathway of Cholesterol and Nonsterol Isoprenoid Biosynthesis

Haas D and Hoffmann G. N Engl J Med 2007;356:2671-2673

 Temporal Patterns of Fever and Associated Clinical Findings in a Patient with Familial
Mediterranean Fever (Panel A), a Patient with the Hyper-IgD Syndrome (Panel B), and a Patient
with the Tumor Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome (Panel C)

Drenth J and van der Meer J. N Engl J Med 2001;345:1748-1757

PYODERMA GANGRENOSUM

Ecthyma-like
Post-surgical

Peristomal-UC Severe
Ulceration Resembling Pyoderma Gangrenosum but Due to Antiphospholipid-Antibody
Syndrome

Weenig R et al. N Engl J Med 2002;347:1412-1418

DD: PYODERMA GANGRENOSUM
Frequency of Diagnostic Findings on Initial or Repeated Biopsy

Weenig R et al. N Engl J Med 2002;347:1412-1418

TABLE 1. Criteria for the diagnosis of adult onset Still's disease
(Yamaguchi et al. 1992 [28]).
Five or more criteria (including two major) required for diagnosis

Major criteria Minor criteria

Fever >39°C Sore throat

Arthralgias Lymphadenopathy or
splenomegaly
Still's rash Hepatic dysfunction
Neutrophilic Negative RF and ANA
leucocytosis

ANA, antinuclear antibody; RF, rheumatoid factor.

Rheumatology 2002; 41: 216-222

 NON EROSIVE CARPAL FUSION

Rheumatology 2002; 41: 216-222

TABLE 2. Positive/abnormal tests

Variable Value

Erythrocyte sedimentation rate (mm/h) 120 (0–20)

C-reactive protein (mg/dl) 21.6 0–0.8
Haemoglobin (g/dl) 7.9 12–15

White blood cell count (x10/mm3) 25.6 3.4–10

Aspartate transaminase (U/L) 88 11–32
Alanine transaminase (U/L) 65 5–30
Lactate dehydrogenase (U/L) 317 110–205
Ferritin (ng/ml) 9846 12–250

Rheumatology 2002; 41: 216-222

TABLE 3.  Negative/normal tests

Antinuclear antibodies Angiotensin converting enzyme concentration

Anti-double-stranded DNA antibodies Anti-cardiolipin antibody
Anti-Smith Familial Mediterranean fever genetic test
Anti-Ro Lyme antibody
Anti-La VDRL test
Anti-RNP Purified protein derivative
C3 Cytomegalovirus (buffy coat, urine)
C4 Human immunodeficiency virus antibody
Rheumatoid factor Cultures: blood, urine, cerebrospinal fluid, bone
ANCA marrow, broncho-alveolar lavage fluid

Serum protein electrophoresis

Creatine kinase

Rheumatology 2002; 41: 216-222

TABLE 4.  Pathology reports

Bone marrow Marked granulocytic hyperplasia; no dysplasia

Liver Patchy periportal inflammation; moderate steatosis
Cervical Non-specific reactive histology
lymph node

Lacrimal gland Normal histology with no lymphoid infiltrate or

evidence of epithelial malignancy

Spleen Follicular hyperplasia; negative for lymphoma

Small intestine Mild villous atrophy; Congo Red stain negative for
amyloid
Rheumatology 2002; 41: 216-222
 Photographs of a four-year-old boy show the typical features of Kawasaki's disease

Trager J. N Engl J Med 1995;333:1391

Photographs of a four-year-old boy show the typical features of Kawasaki's disease

Trager J. N Engl J Med 1995;333:1391

A 14-year-old girl in whom Kawasaki's disease was diagnosed at the age of 2 years had a
posterior myocardial infarction at the age of 3 years

Porter G and Gentles T. N Engl J Med 2001;345:98

Coronary-Artery Aneurysms in a 9-Year-Old Boy, 6 Years after the Diagnosis of Acute Kawasaki
Disease

Burns J. N Engl J Med 2007;356:659-661

SWEET’S SYNDROME ( Acute Febrile Neutrophilic Dermatosis)

Moderate to high fever

Pink eye (conjunctivitis) or sore eyes
Tiredness
Aching joints and headache
Mouth ulcers
INTERLEUKIN-10 PATHWAY
 INTERLEUKIN-10

• anti-apoptosis
• inflammatory response
• immune response
• cytoplasmic sequestering of NF-kappaB
• cell-cell signaling
• hemopoiesis
• B cell differentiation
• leukocyte chemotaxis
• T-helper 2 type immune response
Biological Process:
• B cell proliferation
• negative regulation of T cell proliferation
• defense response to bacterium
• negative regulation of nitric oxide biosynthetic process
• negative regulation of interferon-gamma biosynthetic process
• regulation of isotype switching
• negative regulation of MHC class II biosynthetic process
• positive regulation of MHC class II biosynthetic process
• negative regulation of interferon-alpha biosynthetic process
Recognition of Danger Signals by Dendritic Cells and T-Cell Priming

Jerome, K. R. et al. N Engl J Med 2004;350:411-412

The Receptors Involved in the Interplay of the Innate and Adaptive Immune Systems

Medzhitov R and Janeway C. N Engl J Med 2000;343:338-344

 Chemokines and Their Receptors

Luster, A. D. N Engl J Med 1998;338:436-445

 Innate Immune Mechanisms That Contribute to Autoimmune Disorders

Gregersen P. N Engl J Med 2007;356:1263-1266

GRANULOMA FORMATION
NKT CELLS