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Innate immune system

Last updated: March 31, 2021

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The innate immune system provides an immediate, nonspecific first line of defense against pathogens. It operates based on inherited cellular receptors that respond to broad pathogen-related patterns and common threat signals. The innate immune system develops in utero and, unlike the adaptive (acquired) immune system, does not require imprinting or adaptation to specific antigens nor does it provide permanent pathogen-specific immunity. For this reason, it is also referred to as “nonspecific immunity.” Response to pathogens is rapid, occurring within minutes to hours of exposure. The innate immune system comprises physical, chemical, and biological barriers (e.g., the skin, gastric acid, commensal organisms) and both cellular (e.g., granulocytes, natural killer cells, mast cells) and humoral (complement system) defense mechanisms.

General

Immune cells

Physical barriers

Coughing and sneezing (reflex)

  • Irritation of receptors in nose, sinuses, and lower and upper airways triggers coughing and/or sneezing.
  • Protective mechanisms that serve to remove irritants (e.g., dust) and pathogens through expulsion of air and mucus from the lungs and nasal cavity

Intact skin and mucous membranes (e.g., respiratory tract, genitourinary system, digestive tract)

Biochemical barriers

Production of mucus and body secretions

Mucus and body secretions contain nonspecific and specific protective substances against infections.

Exocytosis of cytotoxic molecules and proteins

Humoral defenses

Key features of innate and adaptive immune systems
Innate immune system Adaptive immune system
Key components
Genetics
  • Germline encoded
  • Does not change over the course of a lifetime
Inheritance
  • Inherited
  • Not inherited
Response time
  • Fast: within minutes to hours
  • Slower (longer lag between antigen exposure and full effect)
Specificity
  • Nonspecific
  • Highly specific, constant expansion over time
Memory response
  • Absent
  • Present
  • Memory response becomes more potent and faster after subsequent exposures to an antigen.
Effector proteins
Recognition

HLA system

Overview of MHC molecules
MHC class I (MHC I) MHC class II (MHC II)
Loci
  • HLA‑A
  • HLA‑B
  • HLA‑C
  • HLA‑DP
  • HLA‑DQ
  • HLA‑DR
Structure
  • Two polypeptide chains of different length
    • Long-chain contains the alpha domains (α1, α2, α3).
    • Short-chain (β2-microglobulin, B2M) contains the β2 domain.
  • Two polypeptide chains of equal length (α and β)
  • Each contain two domains (α1, α2 and β1, β2)
Expression
Function
  • Presentation of intracellular antigens to CD8+ T cells cytotoxic T‑cell reaction → destruction of cells that are infected with intracellular pathogens (endogenous, e.g., viruses) and/or produce atypical proteins (e.g., malignant cells).
Antigen presentation
Associated diseases

MHC I-associated loci (HLA-A/-B/-C) only have 1 letter after the hyphen, while MHC II-associated loci (HLADR/‑DP/‑DQ) have 2 letters.
HLA A3: Fe3+ is increased in HE3mochromatosis.
HLA B8: If you go fishing for HLA, use MAGgots (Myasthenia gravis, Addison disease, Graves disease) for b8 (bait).
HLA B27: They are Both 27 and a PAIR (Psoriatic arthritis, Ankylosing spondylitis, IBD-associated arthritis, Reactive arthritis).
HLA C: Psoriasis is a Cutaneous Condition.

HLA DQ2/DQ8: I 8 2 (ate too) much gluten at Dairy Queen.
HLA DR2: At DooR 2, they sell multiple good hay products (SLE, Multiple sclerosis, Goodpasture syndrome, hay fever).
HLA DR2/DR3: 2, 3, S-L-E.
HLA DR3/DR4: 3,4sugar no more (DM type 1).
HLA DR4: 4 walls make 1rheum” (room).
HLA DR3/DR5: DR. Hashimoto is odd (odd numbers: 3, 5).

Pattern recognition receptors (PRRs)

Respiratory burst (oxidative burst)

Catalase-positive organisms can degrade H2O2 into H2O and O2 and prevent the formation of hydroxyl-halide radicals.

The humoral mechanisms of innate immunity are mediated by proteins that are secreted into bodily fluids or the bloodstream. These proteins often initiate immune responses via:

Acute phase proteins

  • Set of biomarkers whose plasma concentration increases (positive markers, e.g., CRP) or decreases (negative markers, e.g., transferrin) in response to an ongoing inflammatory process.
  • See “Acute phase reaction.”

Complement system

Activation pathways

  • Classical pathway
    • Activated by IgM or IgG complexes binding to the pathogen
    • C1q, C1r, and C1s activation → C1 complex → split of C4 into C4a and C4b and C2 into C2a and C2b → formation of C3 convertase (C4b2b) from C4b and C2b
    • Activation of this pathway can be assessed via the total complement activity test (also called CH50 test).
  • Alternative pathway
    • Activated directly by pathogen surface molecules rather than by antigen-antibody complexes
    • C3 is split into C3a and C3b → binding of factor B → formation of C3 convertase (C3bBb).
  • Lectin pathway
    • Activated by mannose or other sugars on pathogen surface
    • Mannose-binding lectin (MBL) binds to mannose formation of the C1-like complex, which cleaves C4 into C4a and C4b → C4b binding C2 and splitting of C2 into C2a and C2b → formation of C3 convertase (C4b2b).
  • Common end phase

IgG and IgM activate the classic pathway: General Motors (GM) makes classic cars.

Effect

C3b binds to bacteria.

C3a, C4a, C5a lead to mast-cell activation and anaphylaxis.

Inhibition

  • Both decay accelerating factor (DAF, aka CD55) and C1 esterase inhibitor prevent complement activation on body cells (e.g., red blood cells).
Overview of innate immune defects [3][4]
Defective element/complement Associated conditions

Increased susceptibility to

Granulocytes

  • Recurrent nonsuppurative bacterial infections of skin and mucosa
Phagosomes
Complement
  1. Lawrence RA, Lawrence RM. Biochemistry of Human Milk. Elsevier ; 2010 : p. 98-152
  2. Carolina Berger, Suzanne Xuereb, David C. Johnson, Kathe S. Watanabe, Hans-Peter Kiem, Philip D. Greenberg, and Stanley R. Riddell. Expression of Herpes Simplex Virus ICP47 and Human Cytomegalovirus US11 Prevents Recognition of Transgene Products by CD8+ Cytotoxic T Lymphocytes. Journal of Virology. 2000 .
  3. Rosenzweig SD, Holland SM. Recent Insights into the Pathobiology of Innate Immune Deficiencies. Curr Allergy Asthma Rep. 2011; 11 (5): p.369-377. doi: 10.1007/s11882-011-0212-9 . | Open in Read by QxMD
  4. Andrews T, Sullivan KE. Infections in Patients with Inherited Defects in Phagocytic Function. Clin Microbiol Rev. 2003; 16 (4): p.597-621. doi: 10.1128/cmr.16.4.597-621.2003 . | Open in Read by QxMD
  5. Valdez JM, Scheinberg P, Young NS, Walsh TJ.. Infections in patients with aplastic anemia.. Seminars in Hematology. 2009 .
  6. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P . Molecular Biology of the Cell. Garland Science ; 2002
  7. Murphy K, Weaver C. Janeway's Immunobiology. Garland Science ; 2016