Innate or natural or congenital or aspecific immune system

• biologic
• mice, unlike humans, have 2 isoforms of CCL21 that differ in one amino acid; CCL21Ser is expressed by high endothelial venule (HEV), whereas CCL21Leu is generated in the lymphatic endothelium^ref. A mutant mouse strain known as plt/plt (paucity in lymph-node T cells) is deficient for CCL21Ser and CCL19^{ref1, ref2}. LNs of plt/plt mice and CCR7-deficient mice contain few naive T cells, but the B-cell compartment is less affected and there are marked numbers of memory T cells^{ref1, ref2}. This indicated that B cells and perhaps also memory T cells respond to different (or additional) integrin-activating signals in LN HEVs that are not recognized by naive T cells.
• Ag-specific receptors in innate immune system
• Toll-like receptors (TLRs)
• TLR1
• TLR2
• TLR3
• TLR4 binds to LTA
• TLR5
• TLR6
• TLR7 binds to guanosine (G)- and uridine (U)-rich ssRNA oligonucleotides derived from HIV-1^ref
• TLR8 : TLR7-deficient mice are unresponsive to TLR8 agonist IRMs. Similarly, natural ssRNA cannot activate murine TLR8, leading to the belief that murine TLR8 is nonfunctional. HEK293 cells were transfected with murine TLR8 and NF-kB reporter constructs and stimulated them with combinations of IRM and oligodeoxynucleotides (ODNs). When stimulated with TLR7 or TLR8 agonists alone, no NF-kB response was observed. However, a combination of polyT ODN plus the TLR8 agonist activated NF-kB, whereas polyT ODN + the TLR7 agonist did not activate. Primary mouse cells responded to the IRM/polyT ODN by secreting TNF. Cells from TLR7^-/- and TLR9^-/- mice responded to the IRM/polyT ODN combination, whereas MyD88^-/- cells did not respond. In conclusion, this study demonstrates for the first time that mouse TLR8 is functional^ref
• TLR9
• CD1 family members
• Group II only
• CD1d1
• CD1d2 / CD1b
• macrophages : upon activation with LPS, IFN-a/b or IFN-g, they express NKG2D
• dendritic cells (DCs)
• immature DCs
• certain blood monocytes : CD11b / a_M integrin⁺11c⁺45RA^- ‡  + GM-CSF, TNF-a
• tissue interstitial DCs
• Langerhans DC
• mature DCs (common markers : CD11c / a_x integrin⁺40⁺80⁺86⁺ MHC II^mi/hi)

Ontogenesis :
• plasmacytoid DC precursor (CD8a^hi) : t_1/2 = 9 days
• CD4^hi11c / a_x integrin^lo45RA^hi MHC II^lo (equivalent to human pDC2 except for CD11c / a_x integrin^lo45RA^hi MHC II^lo)
• CD4^-8ab^-
• CD2⁺8ab^-IL-3R⁺19^-38⁺43⁺
‡ exogenous stimulus (so not present in uninfected laboratory mice ?)
• mature "lymphoid" DCs : CD4^-/lo8a^hi8b^-11b^-11c / a_x integrin⁺40⁺80⁺86⁺205^hi MHC II^mi/hi
• 70 % total thymic DCs
• 23 % total DCs in T-cell areas of spleen : they cause early apoptotic death in a proportion of the CD4⁺ T cells activated in culture
• 19 % total DCs in mesenteric lymph nodes
• 17 % total DCs in skin-draining LNs
t_1/2 = 1.5 days
They cross-present Ag on MHC I and produce
• IFN-a
• IFN-b
• IL-6
• high levels of IL-12 p70
... able to induce a T_h1-biased cytokine response in reactive CD4⁺ T cells.
• myeloid DCs (CD8a^-)
• mature "myeloid" DCs CD4⁺8a^-8b^-11b⁺11c / a_x integrin^lo40⁺80⁺86⁺205^- MHC II^mi/hi
• 56 % total DCs in marginal zones of spleen, migrate to T-cell zones on stimulation with microbial products
• 4 % total DCs in mesenteric lymph nodes
• 4 % total DCs in skin-draining LNs
They are poor producers of :
• IFN-a
• IFN-b
• IFN-g
... able to induce a T_h2-biased cytokine response in reactive CD4⁺ T cells.
• mature "myeloid" DCs CD4^-8a^-8b^-11b⁺11c / a_x integrin⁺40⁺80⁺86⁺205^- MHC II^mi/hi
• 19 % total DCs in marginal zones of spleen, migrate to T-cell zones on stimulation with microbial products. Sometimes sufficient to induce a T_h1-biased cytokine response in reactive CD4⁺ T cells.
• 37 % total DCs in mesenteric lymph nodes
They produce :
• high levels of IFN-g
• low levels of IL-12 p70
... able to induce a T_h2-biased cytokine response
• mature "myeloid" DCs CD4^-8a^-8b^-11b⁺11c / a_x integrin⁺40⁺80⁺86⁺205^+/mi MHC II^mi/hi
• in all lymph nodes (LNs) : considered the mature form on tissue interstitial DCs
They produce :
• high levels of IFN-g
• low levels of IL-12 p70
• CD4^-8a^-8b^-11b^+/-205⁺ (30 % total DCs in all lymphoid tissues). They produce
• high levels of IFN-g
• low levels of IL-12 p70
Induce a T_h2-biased cytokine response : in spleen sometimes it is sufficient to induce a T_h1-biased cytokine response in reactive CD4⁺ T cells.
• mature "Langerhans" DCs : CD4^-/lo8a^lo8b^-11b⁺11c / a_x integrin⁺40^hi80^hi86^hi205^hi207 / langerin⁺ MHC II^hi (in skin-draining LNs : considered the mature form of Langerhans cells). They cross-present Ag on MHC I and produce
• IFN-a
• IFN-b
• IL-6
• high levels of IL-12 p70
... able to induce a T_h1-biased cytokine response in reactive CD4⁺ T cells.
Please note the terms "lymphoid" and "myeloid" DC no longer denote haematopoietic origin but are still commonly used : both lymphoid-restricted and myeloid-restricted precursors could produce all the mature DC subtypes, so a degree of DC sublineage committment must therefore occur downstream of the early haemotopoietic precursors.
Mouse LNs have at least 6 different DC subsets that are distinguished by differential expression of CD4, CD8a, CD11b, CD11c, CD205 (DEC205), B220, MHC class II and Gr1 (Ly6C/G)^ref1ref2.
• Rodents and other animals have 2 forms of MBP :
• liver-type MBP (L-MBP) / MBP-C (synthetised by hepatocytes and small bowel enterocytes)
• serum-type MBP (S-MBP) / MBP-A (synthetised by hepatocytes, kidney, and small bowel enterocytes)

Acquired or adaptive or specific immune system

• The gastrointestinal nematode parasite Nippostrongylus brasiliensis (Nb) is a well-defined and widely used model for studying T_h2 immune responses. Parasitic larvae migrate into the lungs where they are coughed up and swallowed within 2 days after s.c. inoculation of the infective third-stage larvae (L3). The larvae develop into mature adults that reside in the intestinal lumen and produce eggs that are excreted in the feces. All worms are expelled by ~ 10 days after infection. This acute host-protective primary T_h2 response is associated with increased IgE.
• Ag-specific receptors in adaptive immune system
• receptors binding intracellular Ag : the H-2 complex
Both MHC class I and II genes are inherited as a haplotype on chromosome 17, in the following arrangement :
• H-2 complex
• I region : that part of the H-2 complex containing the immune response genes
• MHC class Ia : K region : H-2K gene product
• MHC class II
• IA region (gene products : IAb ; IAa, IEb)
• IE region (IEa gene product)
• MHC III : S region :
• complement proteins : C2 ; C4 ; B
• TNF-a, TNF-b
• MHC Ia : D region :
• H-2D
• H-2L
• Tla complex
• MHC Ib :
• Tla region
• Qa gene product
• thymic leukemia Ag (TL) (Tla) gene product
• Qa region : there have been suggestions that they contain DNA sequences that can be inserted into the classical class I genes to create new K, D or L genes (gene conversion).
• Qa gene product
• thymic leukemia Ag (TL) (Tla) gene product is noncovalently associated with b₂m and binds to CD8aa homodimers with a 10-fold higher affinity than H-2K^b
• "young TL" model : MHC class Ib genes arise by duplication from MHC class Ia alleles. To achieve the degree of divergence noted, the "young TL" models require that a proto-TL gene would undergo rapid diversigying evolution (positive selection) for some new function, rather than degenerate under neutral evolution.
• "old TL" model : TL is as old as it appears, that is, that it has evolved like a molecular clock. This model leaves unspecified the origin of the proto-TL gene itself, for example, wheter it arose from an ealrly mammalian MHC class Ia allele.
These 2 models differ chiefly in the time of divergence from non-TL MHC genes, and thus the rapidity with which TL must have diverged from a putative MHC class Ia origin. The conserved orthology within the Old World subfamily Murinae strenghtens the hypothesis that TL evolved a specialized function before the divergence of mice and rats and likely at the beginning of the mammalian radiation.
The mouse class I genes, unlike those in humans, are separated by the class II genes A and E in the I region located between K and D. The genes of the different haplotypes would be given peculiar superscript letter names such as K^d or A^k, and the haplotypes (series of genes) are referred to as H-2^d and H-2^k.

Prototype strain	Other strains with the same haplotype	haplotype	H-2 alleles
			K	IA	IE	S	D
CBA	AKR, C3H, B10.BR, C57BR	k	k	k	k	k	k
DBA/2	BALB/c, NZB, SEA, YBR	d	d	d	d	d	d
C57BL/10 (B10)	C57BL/6, C57L, C3H, SW, LP, 129	b	b	b	b	b	b
A	A/He, A/Sn, A/Wy, B10A	a	k	k	k	d	d
A.SW	B10.S, SJL	s	s	s	s	s	s
A.TL		t1	s	k	k	k	d
DBA/1	STOLI, B10.Q, BDP	q	q	q	q	q	q

• receptors binding extracellular Ag
• BcR/Ig/Abs (ABG : germline directories of mouse antibody genes)
• l multigene family (chromosome 16) :
• contains 2 V, 3 functional J (Jl4 is a pseudogene), 3 functional C (coding for the 3 d chain subtypes) and 1 C y in the following arrangement : 5' L, Vl2, Jl2, Cl2, y_Jl4, Cl4, L, Vl1, Jl3, Jl1, Cl1 3'
• k multigene family (chromosome 6 ; The Ig k genes and the k locus of the mouse) :
• about 300 V gene segments, 4 functional J gene segments (plus 1 y), and 1 C gene segment.
• heavy chain multigene family (chromosome 12) :
• 300-1000 L-V gene segments (code for CDR1 and CDR2), 13 D gene segments (along with J gene segments, codes for CDR3), 4 J gene segments, and a series of C gene segments coding for the constant region of each heavy chain isotype.

in the mouse the C heavy gene segments are arranged: m, d, g₃, g₁, g_2b, g_2a, e and a. This sequence corresponds to the developmental appearance of antibody classes during an immune response.
• IgM
• IgD
• IgA
• IgE
• IgGs
• IgG₁
• IgG_2a
• IgG_2b
• IgG₃

(reproduced with permission from Nature Reviews Immunology (Vol 3, No. 11, pp 890-899(2003)) copyright Macmillan Magazines Ltd)
In mice 2 genes encode the VpreB1 and VpreB2 proteins which are 98% structurally identical.
• T_h1-associated isotypes : IgG_2a (homologous to human IgG₁), IgG_2b (homologous to human IgG₃), and IgG₃, induced by IL-12ab, IL-18, and IFN-g, inhibited by ?. TGF-b₁ and IL-21 induce IgG₃, IgG_2b and IgA production.
• T_h2-associated isotypes : IgG₁ and IgE, induced by IL-4 and IL-21, inhibited by IL-12ab, IL-18, and IFN-g
• cells - lymphopoiesis (10⁹ lymphocytes per organism) :
• natural killer (NK) cells / large granular lymphocyte (LGL) (CD3deg^-4^-8ab^-16/FcgRIIIA⁺56⁺85⁺94⁺244⁺, TcR^-) in spleen. There is no mouse counterpart of KIRs encoded by human LRC. Instead the NK gene complex (NKC) on mouse chromosome 6 has a syntenic chromosomal region in humans located on chromosome 12.
• inhibitory receptors : only a single nonfunctional Ly49 gene has been identified in humans.
• Ly49A homodimer (binds MHC class I asymmetrically) --- H-2D1^d
• Ly49C homodimer (binds 2 MHC class I molecules in symmetrical way and does not directly contact the MHC-bound peptide) --- H-2K^b
• Ly49G --- H-2D1^d and H-2K
• Ly49I / NK1.1 homodimers --- H-2D1, H-2K, m157 from MCMV
• CD94 - CD159a / NKG2A heterodimers --- Qa-1^b (a non-polymorphic, nonclassical MHC class I molecule responsible for the recognition of missing-self and the maintenance of self-tolerance of fetal and neonatal NK cells that do not express Ly49)
• KLRH1 --- ?
• activating receptor :
• adapter FceRI g chain or CD247 / x chain (ITAM-containing) => ZAP70/Syk STP
• CD16a/FcgRIIIA --- IgG (mediates ADCC)
• NKp46 --- HA_{Influenzavirus}, ?
• NKR-P1C --- ?
• adapter p14^{DAP12 / KARAP} homodimer (ITAM-containing) => ZAP70/Syk STP
• CD94 - NKG2C --- H-2Q1
• Ly49D -- H-2D1
• Ly49H --- m157 from MCMV
• Ly49P
• Ly49W
• adapter DAP10 (pYXNM-containing) => PI(3)K STP
• NKG2D homodimers (in 70% of Ly49I / NK1.1⁺ T cells; up-regulated by IL-15) --- genes clustered on chromosome 10
• H60 minor histocompatibility antigen (a type-1 transmembrane protein) is the only ligand (K_d = 2 ^. 10^-8 M) that is known to be expressed at high levels by normal adult cells, in particular thymocytes in BALB/c (not C57BL/6) mice. It is probable, however, that the thymus is inaccessible to most mature lymphocytes that are potentially responsive to H60, which might help to explain the failure of these mice to develop H60-induced NK-cell-mediated autoimmunity or tolerance. It is not upregulated during MCMV infection.
• retinoic acid early inducible (RAE) 1 family (Rae1a, Rae1b, Rae1g, Rae1d (K_d = 5 ^. 10^-7 M), and Rae1e (K_d = 2 ^. 10^-8 M)). Developmentally, Rae1-encoding mRNA, especially the Rae1b and Rae1g isoforms, is expressed diffusely throughout early embryos, especially in the brain. By E18, however, expression of the transcripts is downregulated and remains so in all of the normal adult tissues that have been examined, even normally proliferating ones. The expression of Rae1 is upregulated during MCMV infection and in the F9 embryocarcinoma cell line by retinoic acid, but regulation of Rae1 genes by retinoic acid in other cells has not been documented^{ref1, ref2}

[gp40 encoded by the MCMV m152 gene, previously shown to inhibit the expression of MHC class I molecules, also inhibits the expression of Rae1 and possibly other ligands by MCMV-infected cells]
• mouse UL-16-binding protein-like transcript 1 (Mult1) (K_d = 4 ^. 10^-9 M) is expressed at marked levels by various normal cells at the mRNA level, but cell-surface expression by normal cells is low or has not been documented^ref
In pairwise combinations, Rae1, H60, and Mult1 are only 20-28% identical in their amino-acid sequences, but all have a similar and unique domain structure, consisting of 2 ectodomains that are distantly related to the a₁ and a₂ domains of MHC class I molecules, except that the site corresponding to the MHC peptide-binding groove is closed off, apparently preventing the binding of peptides and other small molecules. While structurally different than the human MICA/MICB proteins, the RAE1 and H60 molecules are equally over-expressed on tumors and render cells sensitive to attack by NK cells.
• adapter SAP/SH2D1A
• CD244 / 2B4 --- CD48/Blast-1/OX-45/Hu Lym3
• natural killer T (NKT) cells are defined by co-expression of the NK receptor NK1.1 / Ly49 and TcR :
• category I : Va14Ja18 (formerly either Ja281 or Ja15; forming an invariant CDR3a, but having variable CDR3b regions) preferentially associated with Vb8.2, Vb7 and Vb2 chains, although athere is apparently little or no selection for the CDR3 of the associated b-chain. As the expression of NK1.1 depends on maturity, activation state and tissue location, they are referred as Va14i T cells rather than NKT cells. They are more frequent than are the Va24i T cells in humans. In mice, NKT cells represent up to 30% of the total lymphocytes in the liver, 20% of the TcRab⁺ T cells in the bone marrow, and 3% of the TcRab⁺ T cells in the spleen. There is no counterpart for human Va24⁺CD8⁺ natural killer T (NKT) cells.
• category II has more diverse TcRs that bind undetermined ligands presented in the context of the antigen-presenting molecule CD1d. 2 subsets exist :
• CD4^-8^- (DN)
• CD4⁺
• category III
• category IV
• gd T lymphocytes
• dendritic epidermal T cells (DETC) (NKG2D⁺) are activated through the canonical Vg3Vd1 TcR by Ag expressed by damaged or stressed keratinocytes. Activated DETCs produce KGF-1 / FGF-7, FGF-10, TNF and IFN-g, partecipating in tissue repair. Probably the latter is a conserved function shared by intraepithelial gd T cells in different epithelial tissues.
• iIELs (NKG2D^-)
• splenic gd T lymphocytes (25% are NKG2D⁺)
• CD8⁺ ab T lymphocytes are NKG2D^- before activation.
• CD4⁺ ab T lymphocytes
• they also have T_h4 cells (peanut agglutinin (PNA)^-, high cell electrophoretic mobility) in thymus.
Murine neonates are biased toward T_h2 responses due to T lymphocyte intrinsic properties.
Web resources : Mouse TcRa region project at University of Washington
• Complement cascades
• mouse complement component C4 exists in 2 isoforms :
• C4
• sex-limited protein (Slp), with expression restricted to male animals
• CR1 and CR2 proteins are encoded from alternative splicing of a common transcript of Cr2 gene.

 

 
 

• human CD34⁺ umbilical-cord stem cells injected intrahepatically in conditioned newborn immunodeficient Rag2^-/-g_c^-/- mice produce human dendritic cells, B lymphocytes, and T lymphocytes; after 6 months formation of structured primary and secondary lymphoid organs which are comparable to the human organs and production of a good functional immune response to vaccination with tetanus toxoid or EBV infection occurs^ref. This stem-cell technology, although in its infancy, could recreate a human immune system inside a mouse. Because ethical restrictions limit in vivo studies of the human hemato-lymphoid system, substitute human to small animal xenotransplantation models have been employed : existing models, however, sustain only limited development and maintenance of human lymphoid cells and rarely produce immune responses.
• genetic bias to T_h1 responses^{ref1, ref2}
• B10D2^ref
• C3H/HeJ
• C57BL/6 mice
• genetic bias to T_h2 responses
• BALB/c mice
• DBA/2
• lpr (lymphoproliferation) mice have a transposable element inserted in intron 2 of the Fas / Tnfrsf6 gene, which prevents the transcription of full-length mRNA. Their lupus-like autoimmune syndrome is characterized by progressive lymphadenopathy and autoantibody production, leading to early death from renal failure. Activation of T helper lymphocytes is one of the events in the pathogenesis of the disease in these mice and likely in human systemic lupus erythematosus.
• gld (generalized lymphoproliferative disease) mice have a point mutation within the FasL gene.
• nude or nu/nu mice lack the TF Whn / FoxN1, that leads to hairlessness and epithelial defects, including the loss of a functional thymus (cystic thymic rudiments in adults). Initiation and progression of TEC differentiation are genetically separable functions of Foxn1, and the N-terminal domain is required for crosstalk-dependent TEC differentiation. As they can't reject grafts, they are used as ideal recipients for transplantations (tumours, ...).
• shi (shiverer) mice lack MBP.
• op (osteopetrotic) mice carry a natural point mutation in the M-CSF gene and fail to develop marginal zone macrophages (MZM) in the spleen and the corresponding sinusoidal macrophages in the lymph nodes; these mice are severely deficient in functional osteoclasts and therefore form inadequate bone marrow cavities. Despite these defects, op^-/- mice develop normal in vivo phagocytic functions but have impaired release of TNF and G-CSF. Although B-cell lineage precursors are present in the bone marrow of these mice, B cell lymphopoiesis in adult op^-/- mice is observed only in the liver. Despite this, op^-/- mice demonstrate normal B cell reponses in vivo. Normal MLRs in vitro indicate that T cells from op^-/- mice are functional.
• plt/plt (paucity in lymph-node T cells) is deficient for CCL21Ser and CCL19.
• Syk deficiency causes embryonic lethality : Syk deficiency in lymphocytes is created by reconstituting alymphoid mice with fetal liver cells from Syk^-/-Zap70^-/- embryos
• splotch, carrying a mutaion in the transcription factor paired box gene 3 (Pax3), have defects in derivatives of the somatic mesoderm and neural crest
• Mkp5 / Dusp10-deficient cells produce greatly enhanced levels of pro-inflammatory cytokines during innate immune responses and exhibited greater T-cell activation than their wild-type counterparts. However, Mkp5-deficient T cells proliferated poorly upon activation, which resulted in increased resistance to experimental autoimmune encephalomyelitis. By contrast, Mkp5-deficient CD4⁺ and CD8⁺ effector T cells produced significantly increased levels of cytokines compared with wild-type cells, which led to much more robust and rapidly fatal immune responses to secondary infection with LCMV^ref.
• dual adaptor for phosphotyrosine and 3-phosphoinositides 1 (Dapp1) / Bam32^-/- mice are viable and have normal B-cell development with no differences in splenic B-cell subsets, but a marked reduction in the production of IgG₃ in response to the TI-II antigen TNP-Ficoll and capsule polysaccharides (e.g. from Streptococcus pneumoniae), corresponding with the B-cell autonomous failure to produce g₃ germline transcripts after immunization^ref

 

Tumour line	murine strains	expressed Ig	vaccine formulation
B-cell lymphoma 38C13	C3H/HeN	IgM/k	chimeric Ig: Id-g1/human k
			chimeric Ig fused to GM-CSF
			scFv fused to a IL-1b-derived peptide
			scFv fused to MCP-3 chemokine
			chimeric Ig (Id-g1/human k) in an Ad vector
splenic B-cell lymphoma A31	CBA/Hx  C57B16F1	IgM/k	scFv fused to fragment C of tetanus toxin
			scFv fused to Potexvirus capsid protein
5T33M myeloma	C57BL/Kal  WRij	IgG2b/k	scFv fused to fragment C of tetanus toxin
			scFv fused to Potexvirus capsid protein
A20 B-cell lymphoma	Balb/c	IgG/k	scFv fused to MCP-3 chemokine
BCL1 B-cell lymphoma	Balb/c	IgM/l	chimeric Ig (Id-g1/human k) in an Ad vector
Daudi			CD19+
K562 erythroleukemiaref1, ref2			CD19–

• for B-cells only : only IgM and IgG₃

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