The Immune System

1
The Immune System

• David Colvin, M.D.
• Pediatric Critical Care Medicine
• Clinical Assistant Professor
• Site Director, Sunrise Childrens Hospital
• University of Nevada School of Medicine

2
Immune system hierarchy

• Vertebrates are capable of two types of immune
  responses
• Innate response
• Non-specific and broadly specific recognition and
  action to eliminate the entity
• Adaptive response
• Involving specific recognition and effector
  functions

Tak W. Mak and Mary E. Saunder. The Immune
Response basic and clinical principles. Ch 2
Introduction to the immune response. 2006 Elsevier
3
Immune System Hierarchy

• Innate Immunity
• Non-inducible, non-specific
• Anatomic and physiologic barriers
• Pattern Recognition Molecules/Receptors
• Secreted, endocytic, signaling
• Pathogen-associated molecular paterns (PAMPs)
• Cellular internalization mechanisms
• Macrophages
• Neutrophils
• NK cells

Fuhrman BP, Zimmerman JJ. Pediatric Critical
Care. 3rd ed. Ch 84 Infection and the Host
Response. 2006. Elsevier.
4
Immune System Hierarchy

• Adaptive Immunity
• Lymphocytes
• T B cell receptors somatically generated to
  give each cell unique structure and target
• Specific antibodies
• Not inherited or acquired by natural selection

5
Practice Board Q

• Which of the following statements least
  accurately describes the pattern of
  immunoglobulins (Igs) in the fetus, infant, and
  child?
• The level of IgG in premature infants is directly
  proportional to gestational age in the preterm
  infant.
• IgG levels fall during the first 4 months of
  extra uterine life.
• Adult IgG levels are reached by 4-6 years of age.
• By 10 weeks of intrauterine life, the fetus is
  capable of producing IgM.
• IgA levels peak in children at 1 year of age.

6
Practice Board Q

• E The developmental pattern of immunoglobulins
  (Igs) is as follows
• IgG transfer across the placenta occurs as early
  as 8 weeks gestational age. Its level is directly
  proportional to gestational age, but is still
  less than 50 of term levels at 28 weeks
  gestation. The IgG levels fall during the first
  four months of extrauterine life reaching adult
  levels by 4-6 years of age.
• By the 10th week of gestation, the fetus is
  capable of producing IgM and may make large
  quantities in the presence of a congenital
  infection.
• IgA is not measurable until late in gestational
  life and is very limited in the infant, failing
  to reach adult values until puberty.
• (Rogers MC, et al. Textbook of Pediatric
  Intensive Care, 3rd Edition p. 916.)

7
ABP Guidelines

• Infectious Disease, Immunology, and Inflammation
  A.Structure, function, and development1.Host
  defenses a.Generala.Chronic50b.c.d.Distinguish
  among the specific immune functions performed by
  the components of the innate immune system and
  the acquired immune systemKnow the importance of
  endothelial/epithelial barriers as defense
  against infectionKnow the structure and
  development of the components of the
  immune/inflammation systemUnderstand the
  pathogenesis of feverUnderstand the biochemistry
  of inducible nitric oxideUnderstand the
  production and effects of inducible nitric
  oxideUnderstand disseminated intravascular
  coagulation as a component of the innate immune
  responseUnderstand the role of toll-like
  receptors in the initiation of the innate immune
  responseUnderstand the role of the transcription
  factor NF-kB in the initiation and amplification
  of the immune responseUnderstand the importance
  of the circulating proteins of the innate immune
  system (eg, lectins, C3, LPS-binding proteins,
  acute phase reactants, etc)Understand the
  importance of the cellular components of the
  innate immune system (eg, phagocytes, natural
  killer cells)Understand the role of endothelial
  cells in the innate immune responsePhagocytic
  systemUnderstand the function of the phagocytic
  systemUnderstand the role of oxygen metabolites
  in killing by phagocytesUnderstand the mechanisms
  by which endothelium and phagocytic cells
  interactUnderstand the functions of macrophages,
  neutrophils, eosinophils, and basophilsReticuloend
  othelial system (see VIII.B.4)Understand the role
  of the reticuloendothelial systemLymphocytic
  systemKnow the immune function of the B-cell
  system51e.f.Know the immune function of the
  immunoglobulinsPlateletsKnow that activated
  platelets produce the vasoconstrictor thromboxane
  A2Understand the role of platelets in the immune
  systemHumoral immune/inflammatory
  systemUnderstand the role of the complement
  systemKnow that the membrane lipids are a source
  for eicosanoids and platelet-activating
  factorKnow the lipid-derived mediators of
  inflammation and their effects Understand the
  role of cytokines in inflammation Understand the
  role of oxyradicals in inflammation Understand
  the role of nitric oxide in inflammationUnderstand
  the role of adhesive glycoproteins in
  inflammation Know the signs of inflammation
  Understand the role of cytokines in stimulating
  leukocyte growth2.Immune dysfunctiona.b.c.d.Genera
  lRecognize manifestations of dysfunction of the
  several components of the normal immune
  systemKnow how to evaluate a patient for specific
  immune deficienciesIatrogenicKnow iatrogenic
  causes of immune system dysfunction including
  anesthetic agents, trauma, and surgeryNutritionalR
  ecognize the relationship between malnutrition
  and immune dysfunctionInfectious immune
  depressionRecognize the patient at risk for
  immune suppression secondary to an infectious
  52Know the immune function of the T-cell
  systemdiseasee.IntegumentKnow the pathogens that
  typically infect defective or injured
  integumentKnow the life-threatening complications
  of skin infectionf.Endothelial barriersRecognize
  endothelial barrier failure as a possible cause
  of sepsisRecognize gastrointestinal endothelial
  injury/translocation as a cause of
  sepsis/inflammationg.B-cell system/immunoglobulins
  Recognize the manifestations of B-cell
  dysfunction in an acutely ill patient Identify
  the pathogens to which a patient with B- cell
  deficiency is susceptible Identify the disorders
  associated with B-cell deficiency Recognize
  immunoglobulin deficiencyh.T-cell systemRecognize
  the manifestations of T-cell dysfunction in an
  acutely ill patient Identify the pathogens to
  which a patient with T-cell deficiency is
  susceptible Recognize the manifestations of
  severe combined immunodeficiency syndrome
  Identify the disorders associated with T-cell
  deficiencyi.Phagocytic systemRecognize the
  manifestations of dysfunctional or deficient
  phagocytosis in an acutely ill patientIdentify
  the pathogens to which a patient with defective
  or deficient phagocytosis is susceptibleRecognize
  the clinical features of chronic granulomatous
  diseaseIdentify the pathogens to which patients
  with chronic granulomatous disease are
  particularly susceptibleIdentify the disorders
  associated with phagocytic system
  dysfunctionUnderstand the pathogenesis of chronic
  granulomatous diseasej.Complement
  system53Recognize the manifestations of deficient
  complement activityk.Reticuloendothelial
  systemRecognize the manifestations of dysfunction
  of the reticuloendothelial system in an acutely
  ill patientIdentify the pathogens to which a
  child with defective or deficient
  reticuloendothelial function is susceptibleKnow
  the disorders that cause defective or deficient
  reticuloendothelial functionl.Acquired
  immunodeficiency syndrome (AIDS)
  (1).PathophysiologyUnderstand the pathophysiology
  of AIDS(2).Clinical courseKnow the natural
  history of AIDS Know the natural history of
  congenital infection with HIV type 1 Understand
  how human immunodeficiency virus (HIV) is
  acquired(3).DiagnosisRecognize the common
  clinical presentations of HIV type 1
  infectionUnderstand the interpretation of
  laboratory tests used in the diagnosis of HIV
  type 1 infection(4).Life-threatening
  complicationsRecognize the manifestations of
  life-threatening complications of AIDSIdentify
  the bacterial pathogens to which a child with
  AIDS is particularly susceptibleKnow the common
  causes of respiratory failure in a child with
  AIDSIdentify the viral pathogens to which a child
  with AIDS is particularly susceptibleIdentify the
  other pathogens (not viral or bacterial) to which
  a child with AIDS is particularly
  susceptible(5).TreatmentPlan appropriate
  management for critically ill patients with AIDS

8
ABP Guidelines

• Infectious Disease, Immunology, and Inflammation
  A.Structure, function, and development1.Host
  defenses a.Generala.Chronic50b.c.d.Distinguish
  among the specific immune functions performed by
  the components of the innate immune system and
  the acquired immune systemKnow the importance of
  endothelial/epithelial barriers as defense
  against infectionKnow the structure and
  development of the components of the
  immune/inflammation systemUnderstand the
  pathogenesis of feverUnderstand the biochemistry
  of inducible nitric oxideUnderstand the
  production and effects of inducible nitric
  oxideUnderstand disseminated intravascular
  coagulation as a component of the innate immune
  responseUnderstand the role of toll-like
  receptors in the initiation of the innate immune
  responseUnderstand the role of the transcription
  factor NF-kB in the initiation and amplification
  of the immune responseUnderstand the importance
  of the circulating proteins of the innate immune
  system (eg, lectins, C3, LPS-binding proteins,
  acute phase reactants, etc)Understand the
  importance of the cellular components of the
  innate immune system (eg, phagocytes, natural
  killer cells)Understand the role of endothelial
  cells in the innate immune responsePhagocytic
  systemUnderstand the function of the phagocytic
  systemUnderstand the role of oxygen metabolites
  in killing by phagocytesUnderstand the mechanisms
  by which endothelium and phagocytic cells
  interactUnderstand the functions of macrophages,
  neutrophils, eosinophils, and basophilsReticuloend
  othelial system (see VIII.B.4)Understand the role
  of the reticuloendothelial systemLymphocytic
  systemKnow the immune function of the B-cell
  system51e.f.Know the immune function of the
  immunoglobulinsPlateletsKnow that activated
  platelets produce the vasoconstrictor thromboxane
  A2Understand the role of platelets in the immune
  systemHumoral immune/inflammatory
  systemUnderstand the role of the complement
  systemKnow that the membrane lipids are a source
  for eicosanoids and platelet-activating
  factorKnow the lipid-derived mediators of
  inflammation and their effects Understand the
  role of cytokines in inflammation Understand the
  role of oxyradicals in inflammation Understand
  the role of nitric oxide in inflammationUnderstand
  the role of adhesive glycoproteins in
  inflammation Know the signs of inflammation
  Understand the role of cytokines in stimulating
  leukocyte growth2.Immune dysfunctiona.b.c.d.Genera
  lRecognize manifestations of dysfunction of the
  several components of the normal immune
  systemKnow how to evaluate a patient for specific
  immune deficienciesIatrogenicKnow iatrogenic
  causes of immune system dysfunction including
  anesthetic agents, trauma, and surgeryNutritionalR
  ecognize the relationship between malnutrition
  and immune dysfunctionInfectious immune
  depressionRecognize the patient at risk for
  immune suppression secondary to an infectious
  52Know the immune function of the T-cell
  systemdiseasee.IntegumentKnow the pathogens that
  typically infect defective or injured
  integumentKnow the life-threatening complications
  of skin infectionf.Endothelial barriersRecognize
  endothelial barrier failure as a possible cause
  of sepsisRecognize gastrointestinal endothelial
  injury/translocation as a cause of
  sepsis/inflammationg.B-cell system/immunoglobulins
  Recognize the manifestations of B-cell
  dysfunction in an acutely ill patient Identify
  the pathogens to which a patient with B- cell
  deficiency is susceptible Identify the disorders
  associated with B-cell deficiency Recognize
  immunoglobulin deficiencyh.T-cell systemRecognize
  the manifestations of T-cell dysfunction in an
  acutely ill patient Identify the pathogens to
  which a patient with T-cell deficiency is
  susceptible Recognize the manifestations of
  severe combined immunodeficiency syndrome
  Identify the disorders associated with T-cell
  deficiencyi.Phagocytic systemRecognize the
  manifestations of dysfunctional or deficient
  phagocytosis in an acutely ill patientIdentify
  the pathogens to which a patient with defective
  or deficient phagocytosis is susceptibleRecognize
  the clinical features of chronic granulomatous
  diseaseIdentify the pathogens to which patients
  with chronic granulomatous disease are
  particularly susceptibleIdentify the disorders
  associated with phagocytic system
  dysfunctionUnderstand the pathogenesis of chronic
  granulomatous diseasej.Complement
  system53Recognize the manifestations of deficient
  complement activityk.Reticuloendothelial
  systemRecognize the manifestations of dysfunction
  of the reticuloendothelial system in an acutely
  ill patientIdentify the pathogens to which a
  child with defective or deficient
  reticuloendothelial function is susceptibleKnow
  the disorders that cause defective or deficient
  reticuloendothelial functionl.Acquired
  immunodeficiency syndrome (AIDS)
  (1).PathophysiologyUnderstand the pathophysiology
  of AIDS(2).Clinical courseKnow the natural
  history of AIDS Know the natural history of
  congenital infection with HIV type 1 Understand
  how human immunodeficiency virus (HIV) is
  acquired(3).DiagnosisRecognize the common
  clinical presentations of HIV type 1
  infectionUnderstand the interpretation of
  laboratory tests used in the diagnosis of HIV
  type 1 infection(4).Life-threatening
  complicationsRecognize the manifestations of
  life-threatening complications of AIDSIdentify
  the bacterial pathogens to which a child with
  AIDS is particularly susceptibleKnow the common
  causes of respiratory failure in a child with
  AIDSIdentify the viral pathogens to which a child
  with AIDS is particularly susceptibleIdentify the
  other pathogens (not viral or bacterial) to which
  a child with AIDS is particularly
  susceptible(5).TreatmentPlan appropriate
  management for critically ill patients with AIDS

9
ABP Guidelines

• Innate Immune System
• Understand the role of toll-like receptors in the
  initiation of the innate immune response
• Understand the role of the transcription factor
  NF-kB in the initiation and amplification of the
  immune response
• Understand the importance of the circulating
  proteins of the innate immune system

THE AMERICAN BOARD OF PEDIATRICS CONTENT
OUTLINE Pediatrics https//www.abp.org/abpwebsit
e/certinfo/subspec/suboutlines/crit2010.pdf Page
54 of 172
10
Toll Like Receptors (TLRs)

• Christiane Nüsslein-Volhard, Max Planck Institute
  in Tübingen, Das war ja toll!
• 1995 Nüsslein-Volhard win Nobel Prize
• Found to play role in development of sidedness in
  Drosophila melanogaster and later found to play
  essential role in flys immunity to fungal
  infection
• Toll receptor first noted to play role in
  drosophila immune function in 1996 by Jules A.
  Hoffmann

Hoffmann, et al. The Dorsoventral Regulatory
Gene Cassette spatzle/Toll/cactus Controls the
Potent Antifungal Response in Drosophila Adults.
Cell, Vol. 86, 973-983, September 20, 1996
11
TLRs

• Ancient but new
• Most recently characterized component of innate
  immune system
• Found in simple/ancient species

12
TLRs

• First human Toll-Like receptor described by
  Nomura in 1994 and gene mapped in 1996
• Similarities in cytoplasmic portion of receptor
  molecules noted between Toll in drosophila and
  mammalian IL-1
• Toll found to activate immune response to fungal
  ellements in Drosphila
• Human TLR4 found to be analog to Toll

Nomura N, et al. Prediction of the coding
sequences of unidentified human genes... DNA Res.
1 (1) 27-35.1994
13
TLRs

• In 1997, Charles Janeway and Ruslan Medzhitov
  found TLR4 could induce activation of genes
  involved in an adaptive immune response
• Bruce A. Beulter and colleagues classified more
  TLRs
• TLRs detect molecules of microbial origin and
  activate signal pathways to alert the immune
  system.
• 13 TLRs characterized so far and many create
  homo- dimers and heterodimers

Medzhitov R, Preston-Hurlburt P, Janeway CA
(July 1997). A human homologue of the Drosophila
Toll protein signals activation of adaptive
immunity. Nature 388 (6640) 394-7
14
TLRs
TLR 2
TLR 4
http//en.wikipedia.org/wiki/FileTLR3_structure.p
ng
15
TLRs
Tak W. Mak and Mary E. Saunder. The Immune
Response basic and clinical principles. Ch 2
Introduction to the immune response. 2006
Elsevier Information based on my unpublished
research
16
TLR 4

• Human analogue to original Toll receptor in
  Drosophila
• Recognizes LPS on APCs
• TLR4 is needed (along with CD14) in order to
  mount LPS-dependent innate immune response
• Intracellular cascade resulting from Toll/IL-1
  receptor (TIR) adaptor molecules
• MYD88/MAL-TRIP, TRAM, TRIF
• NFkB
• STAT1 Activator Protein 1 (AP-1)
• Transcription of TNF, IFN-?

17
TLRs
McGettrick AF, ONeill LA. Toll-like receptors
key activators of leucocytes and regulaot of
haematopeisis. BJH review 2007139185-193
18
TLR 3

• Discovered in 2001 by Alexopoulou, et all
• aka CD283
• Present within endocytic vesicles of dendritic
  cells and on surface of epithelial cells
• Recognizes double-stranded RNA ? NF-kB ? cell
  mediated immune response
• Mammalian mRNA also found to complex with
  proteins and bind with TLR3 possibly initiating
  an inflammatory response to host tissues

Alexopoulou L, Holt AC, Medzhitov R, Flavell RA
(2001). "Recognition of double-stranded RNA and
activation of NF-kappaB by Toll-like receptor 3".
Nature 413 (6857) 732-8
19
Circulating Proteins of the Innate Immune System

• Acute Phase Reactants
• Cytokines
• Complement

20
Practice Board Q

• Which is true regarding the cell-mediated effects
  of antigenic challenge?
• Antigen is processed by the macrophage with
  presentation to the T-cell (vesting) to produce
  J-interferon, interleukins, and B-cells
  differentiating factor.
• The B-cell is activated by antigen to produce
  antibody-secreting cells.
• T-cells comprise 55-75 of the lymphocyte
  population.
• IgG and IgM are potent bacterial organ opsonins
  which activate complement via the classical
  pathway.
• All of the above.

21
Answer

• E All of the above.
• Of the total lymphocyte population, 55-75 are
  T-cells. B-cells are activated by antigen to
  secrete antibody. IgG and IgM are the only Ig
  classes that are capable of activating the
  classical complement pathway.
• (Rogers MC, et al. Textbook of Pediatric
  Intensive Care, 3rd Edition pp. 568,569.)

22
C Reactive Protein (CRP)

• Calcium-dependent ligand binding protein
• Produced by hepatocytes
• Released in response to inflammatory mediators
• Infection
• Allergic conditions
• Inflammatory disease
• Necrosis
• Trauma
• Malignancy

23
CRP as serum marker

• Non-specific release
• Peak in 2-3 days
• May take as long as 3 weeks to return to baseline
• IL-6 may be more sensitive marker for sepsis than
  CRP or ESR

Berbari E, et al. Inflammatory Blood Laboratory
Levels as Markers of Prosthetic Joint Infection
A Systematic Review and Meta-Analysis. JBJS
2010922102-2109
24
CRP

• Binds to cell wall components of bacteria, fungi,
  parasites
• Glycan
• Phospholipids
• Phosphocholine (necrotic/apoptotic cells)
• When bound to circulating ligands, activates
  compliment cascade
• Binds C1q of classic pathway
• Initiation of cell death

Fuhrman BP, Zimmerman JJ. Pediatric Critical
Care. 3rd ed. Ch 84 Infection and the Host
Response. 2006. Elsevier.
25
Cytokines

• Signaling proteins secreted by cells that affect
  the functional properties of other cells of the
  same organism.
• Proteins, glycoprotines or peptides
• Interleukins, chemokines, or lymphokines
• Structural distinctions
• 4 ?-helix family
• IL-2 family
• INF family
• IL-10 family

Fuhrman BP, Zimmerman JJ. Pediatric Critical
Care. 3rd ed. Ch 84 Infection and the Host
Response. 2006. Elsevier.
26
Cytokines

• Low molecular weight proteins (lt80kDa)
• Similar to hormones
• Travel shorter distances
• Effect cells in autocrine/exocrine/endocrine
  fashion
• Much more robust increase in serum concentration
  in response to stimulation
• High affinity interaction with specific
  cell-surface receptors --gt effect gene
  expression/protein production

27
Practic Board Q

• All of the following statements regarding immune
  system physiology are true except
• The alternative pathway is activated by bacterial
  cell wall components via interaction withC3b.
• C3a and C5a are chemotactic for neutrophils.
• C5 is important in fungal infection control.
• C6-9 are necessary for control of Neisseria
  infections.
• A selective lack of B-cells is seen in DiGeorge
  Syndrome.

28
Practice Board Q

• E
• DiGeorge Syndrome includes clinical features of
  thymic aplasia, parathyroid aplasia, and
  conotruncal cardiac defects. The deficiency of
  cell mediated immunity in DiGeorge is a result of
  the thymic aplasia, and a relative absence of
  T-cells not B- cells. All of the other responses
  are true.
• (Rogers MC, et al. Textbook of Pediatric
  Intensive Care, 3rd Edition pp. 931,932.)

29
IL-1

• Early mediator of endotoxic shock
• Produced by
• Macrophages
• Endothelial Cells
• Epithelial Cells
• Vas. Smooth M. Cells
• Precursor molecule cleaved by Caspase 1
• (IL-1? converting enzyme)
• 2 forms
• IL-1?
• IL-1?

• IL-1 receptor antagonist (RA)
• Only IL inhibitor
• Produced by same cells as IL-1
• Monoclonal IL-1 RA may be therapy for conditions
  with dysregulated cytokine production

30
IL-2

• Important for development of adaptive immune
  response
• Produced by CD4 T helper cells once MHC binds
  foreign peptides and activate
• Triggers T cell proliferation and differentiation
  into effector T cells
• Both autocrine and paracrine function

31
IL 6

• Most important interleukin for production of
  acute phase reactants
• Produced by many different cells in body
• Mostly by macrophages
• Primarily acts on hepatocytes
• May be useful serum marker for inflammation

32
IL-12

• Stimulates T and NK cells
• Proliferation
• Cytokine production
• Cytotoxic activity
• Polarizes T cells to Th1 phenotype
• Produced by monocytes, macrophages, DCs, B cells
  and neutrophils
• Neonates have decreased IL-12
• Human deficiency leads to susceptibility to
• Salmonella
• Mycobacterium

33
IL-18

• Stimulates IFN-? production
• Endotoxic shock
• Myocardial suppression in shock
• Modulation of NO production
• Produced by macrophages/monocytes
• Effects on activated T cells, stimulated
  macrophages
• Important for controling infections by
• Salmonella
• Cryptococcus
• Toxoplasma
• Candida
• Mycobacterium

34
Tumor Necrosis Factor

• TNF-? and TNF-?(lymphokine)
• Early mediator of endotoxin shock
• Implicated in CHF, cardiomyopathy with sepsis
• Produced by NK cells, Monocytes, Macrophages,
  Mast cells, multiple tissues
• Precursor molecule cleaved
• TNF-? converting enzyme (TACE/ADAM17)
• Low level production in minor injury/infection
• Monoclonal ab (infliximab)
• Fusion protien of TNF receptor and IGg1
  (Etanercept)

35
Interferons

• Type I IFN-?, IFN-?
• IFN-? produced by Mono/Macrophages
• IFN-? produced by fibroblasts
• Stimulated by viral infections adaptive immune
  signals
• Anti-viral effects
• Inhibit host cell proliferation
• Enhance NK cell function
• Increase HLA class 1 and decrease HLA class 2
  antigens

36
Interferons

• Type II IFN-?
• Produced by CD4, CD8 and NK cells
• Primarily antiviral activities
• Decreases host-cell proliferation
• Up regulates Class 1 HLA, down regulates Class 2
  HLA
• Antibacterial activity as well
• Stimulates Monocytes/Macrophages and Neutrophils
  to enhance killing of infected cells
• Induces inducible NO synthase in macrophages

37
A few more Cytokines

• High Mobility Group Box 1 (HMGB1)
• Macrophage Migration Inhibitory Factor (MIF)
• Colony stimulating factors (GSF)
• Nitric Oxide
• Platelet Factors (PF)
• VEGF
• TGF ?/?
• Heat Shock Proteins (HSPs)

38
Stick with me
39
Compliment System

• Classical Pathway
• Alternative Pathway
• Mannose-binding Lectin Pathway

40
Compliment System

• Classic Pathway
• Initiated by binding of C1 complex
• C1q,C1r,C1s
• Cell wall antibodies
• C1s activates C4 then C2 ?C4b2a
• C3 convertase

41
Compliment System

• Alternative Pathway
• Low grade cleavage of C3 to C3b in serum
• Initiated by binding of C3b to
• Bacterial products
• Yeast products
• Aggregated IgA/E
• C3b binds to factor B ?C3bB
• Activation by Factor D to C3bBb (C3 convertase)

42
Compliment System

• Mannose-binding Lectin Pathway
• Initiated by binding to Mannose-binding
  lectin-associated proteases 1 and 2 (MASP1/2) to
  bacterial cell wall manose groups
• MASP 2 activates C4 ?C2
• Formation of C3 convertase (C4bC2a)

43
Complement System

• Classic Pathway
• Initiated by binding of C1 complex
• C1q,C1r,C1s
• Cell wall antibodies
• Mannose-binding Lectin Pathway
• Initiated by binding to Mannose-binding
  lectin-associated proteases 1 and 2 (MASP1/2) to
  arrays of bacterial cell wall manose groups

• Alternative Pathway
• Low grade cleavage of C3--gtC3b in serum
• Initiated by binding of C3b to
• Bacterial products
• LPS
• Yeast products
• Aggregated IgA/E

44
Complement System

• All three systems converge at the cleavage of
  C3?C3a/b, C2a, C4b?C5-9?MAC
• C3b binds to bacteria in area of activation
• Formation of C3bB complex leads to increased C3
  cleavage (Amplification)
• C3b-C3b-Bb forms C5 convertase
• Releases C5a (anaphylaxatoxin)
• Initiates MAC formation (C3b-C9)
• Poor formation leads to cell death
• Opsonization with complement fragments and local
  inflammation lead to phagocytosis

45
Complement System

• Major component of innate immunity
• Bridges the gap to adaptive immunity
• (Complements immunoglobulins)
• Complement proteins in plasma amount to more than
  3 g/L and approximately 15 of the globulin
  fraction
• Some viruses mimic or incorporate complement
  proteins to gain entry into cells
• Disorders of complement regulation may lead to
• Susceptibility to infection (Neisseria)
• Glomerulonephritis (C3 Nephritic factor)
• Angioedema (C1 inhibitor deficiency)

Walport MJ. Complement. The New England Journal
of Medicine.2001Vol. 344, No. 141058-1066
46
References

• All board questions and answers taken from
• Hasan RA, Pappas MD. Pediatric Critical Care
  Review Ch. 9 Immunology. 2006 Humana Press.
• Alexopoulou L, Holt AC, Medzhitov R, Flavell RA
  (2001). "Recognition of double-stranded RNA and
  activation of NF-kappaB by Toll-like receptor 3".
  Nature 413 (6857) 732-8
• Fuhrman BP, Zimmerman JJ. Pediatric Critical
  Care. 3rd ed. Ch 84 Infection and the Host
  Response. 2006. Elsevier.
• Hoffmann, et al. The Dorsoventral Regulatory Gene
  Cassette spatzle/Toll/cactus Controls the Potent
  Antifungal Response in Drosophila Adults. Cell,
  Vol. 86, 973-983, September 20, 1996
• McGettrick AF, ONeill LA. Toll-like receptors
  key activators of leucocytes and regulaot of
  haematopeisis. BJH review 2007139185-193
• Medzhitov R, Preston-Hurlburt P, Janeway CA (July
  1997). A human homologue of the Drosophila Toll
  protein signals activation of adaptive immunity.
  Nature 388 (6640) 394-7
• Nomura N, et al. Prediction of the coding
  sequences of unidentified human genes... DNA Res.
  1 (1) 27-35.1994
• Tak W. Mak and Mary E. Saunder. The Immune
  Response basic and clinical principles. Ch 2
  Introduction to the immune response. 2006
  Elsevier
• Walport MJ. Complement. The New England Journal
  of Medicine.2001Vol. 344, No. 141058-1066

47
Thank You