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The Extracellular Domains of IgG1 and T Cell-Derived IL-4/IL-13 Are Critical for the Polyclonal Memory IgE Response In Vivo.

Turqueti-Neves A, Otte M, Schwartz C, Schmitt ME, Lindner C, Pabst O, Yu P, Voehringer D - PLoS Biol. (2015)

Bottom Line: The development and persistence of IgE responses are poorly understood, which is in part due to the low number of IgE-producing cells.Together, our results reveal a close relationship between the IgE and IgG1 repertoires in vivo and demonstrate that the memory IgE response is mainly conserved at the level of memory IgG1+ B cells.Therefore, targeting the generation and survival of allergen-specific IgG1+ B cells could lead to development of new therapeutic strategies to treat chronic allergic disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Infection Biology, Institute for Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

ABSTRACT
IgE-mediated activation of mast cells and basophils contributes to protective immunity against helminths but also causes allergic responses. The development and persistence of IgE responses are poorly understood, which is in part due to the low number of IgE-producing cells. Here, we used next generation sequencing to uncover a striking overlap between the IgE and IgG1 repertoires in helminth-infected or OVA/alum-immunized wild-type BALB/c mice. The memory IgE response after secondary infection induced a strong increase of IgE+ plasma cells in spleen and lymph nodes. In contrast, germinal center B cells did not increase during secondary infection. Unexpectedly, the memory IgE response was lost in mice where the extracellular part of IgG1 had been replaced with IgE sequences. Adoptive transfer studies revealed that IgG1+ B cells were required and sufficient to constitute the memory IgE response in recipient mice. T cell-derived IL-4/IL-13 was required for the memory IgE response but not for expansion of B cells from memory mice. Together, our results reveal a close relationship between the IgE and IgG1 repertoires in vivo and demonstrate that the memory IgE response is mainly conserved at the level of memory IgG1+ B cells. Therefore, targeting the generation and survival of allergen-specific IgG1+ B cells could lead to development of new therapeutic strategies to treat chronic allergic disorders.

No MeSH data available.


Related in: MedlinePlus

Overlapping IgE repertoires in different organs after primary and secondary N. brasiliensis infection.(A) Heat maps for the first 50 most frequent CDR3 sequences in the IgE repertoires from bone marrow (BM), lung (LU), spleen (SP), and lymph nodes (LN) of one exemplary N. brasiliensis-infected mouse after primary (1st) and secondary infection (2nd). Each row indicates one unique CDR3 sequence ordered by decreasing frequency in the IgE pools of BM, LU, SP, and LN (left to right). The brightest green indicates an abundance of ≥1% of a particular CDR3 sequence. (B) Morisita-Horn indices show the relatedness between 1,000 randomly chosen CDR3 sequences of IgE in the indicated organs after primary and secondary infection. (C) Number of different CDR3 in 1,000 randomly chosen IgE sequences from indicated organs after primary and secondary infection. (D) Frequencies of SHMs in VH regions of IgE in indicated organs after primary and secondary infection. Data in (B) and (C) show the mean + SEM from two mice per experiment.
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pbio.1002290.g006: Overlapping IgE repertoires in different organs after primary and secondary N. brasiliensis infection.(A) Heat maps for the first 50 most frequent CDR3 sequences in the IgE repertoires from bone marrow (BM), lung (LU), spleen (SP), and lymph nodes (LN) of one exemplary N. brasiliensis-infected mouse after primary (1st) and secondary infection (2nd). Each row indicates one unique CDR3 sequence ordered by decreasing frequency in the IgE pools of BM, LU, SP, and LN (left to right). The brightest green indicates an abundance of ≥1% of a particular CDR3 sequence. (B) Morisita-Horn indices show the relatedness between 1,000 randomly chosen CDR3 sequences of IgE in the indicated organs after primary and secondary infection. (C) Number of different CDR3 in 1,000 randomly chosen IgE sequences from indicated organs after primary and secondary infection. (D) Frequencies of SHMs in VH regions of IgE in indicated organs after primary and secondary infection. Data in (B) and (C) show the mean + SEM from two mice per experiment.

Mentions: We further analyzed the overlap of the IgE repertoires in bone marrow, lung, spleen, and LN after primary and secondary infection by NGS analysis to determine the clonal dissemination of IgE+ PCs in these tissues. During primary infection, the IgE repertoires in lung, LN, and spleen showed pronounced overlaps, while the IgE repertoire in the bone marrow was rather unique. However, an increased overlap between the IgE repertoire in the bone marrow and the other organs was observed after secondary infection (Fig 6A and 6B). The IgE repertoires had a high diversity with 300–400 different sequences among 1,000 analyzed sequences in lung, spleen, and LN during primary or secondary infection, whereas the diversity was 2–3-fold lower in the bone marrow (Fig 6C). Similar to the primary infection, the majority of sequences used the VH1/J558 family in combination with DH1 or DH2 segments (S4 and S5 Fig). By analyzing the number of SHMs in the VH region of productive sequences, we observed that during primary infection about 50% of all IgE sequences in all organs contained 0–3 SHMs. During secondary infection, the repertoires were dominated by sequences with 3–20 SHMs reflecting further selection and affinity maturation (Fig 6D).


The Extracellular Domains of IgG1 and T Cell-Derived IL-4/IL-13 Are Critical for the Polyclonal Memory IgE Response In Vivo.

Turqueti-Neves A, Otte M, Schwartz C, Schmitt ME, Lindner C, Pabst O, Yu P, Voehringer D - PLoS Biol. (2015)

Overlapping IgE repertoires in different organs after primary and secondary N. brasiliensis infection.(A) Heat maps for the first 50 most frequent CDR3 sequences in the IgE repertoires from bone marrow (BM), lung (LU), spleen (SP), and lymph nodes (LN) of one exemplary N. brasiliensis-infected mouse after primary (1st) and secondary infection (2nd). Each row indicates one unique CDR3 sequence ordered by decreasing frequency in the IgE pools of BM, LU, SP, and LN (left to right). The brightest green indicates an abundance of ≥1% of a particular CDR3 sequence. (B) Morisita-Horn indices show the relatedness between 1,000 randomly chosen CDR3 sequences of IgE in the indicated organs after primary and secondary infection. (C) Number of different CDR3 in 1,000 randomly chosen IgE sequences from indicated organs after primary and secondary infection. (D) Frequencies of SHMs in VH regions of IgE in indicated organs after primary and secondary infection. Data in (B) and (C) show the mean + SEM from two mice per experiment.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4629909&req=5

pbio.1002290.g006: Overlapping IgE repertoires in different organs after primary and secondary N. brasiliensis infection.(A) Heat maps for the first 50 most frequent CDR3 sequences in the IgE repertoires from bone marrow (BM), lung (LU), spleen (SP), and lymph nodes (LN) of one exemplary N. brasiliensis-infected mouse after primary (1st) and secondary infection (2nd). Each row indicates one unique CDR3 sequence ordered by decreasing frequency in the IgE pools of BM, LU, SP, and LN (left to right). The brightest green indicates an abundance of ≥1% of a particular CDR3 sequence. (B) Morisita-Horn indices show the relatedness between 1,000 randomly chosen CDR3 sequences of IgE in the indicated organs after primary and secondary infection. (C) Number of different CDR3 in 1,000 randomly chosen IgE sequences from indicated organs after primary and secondary infection. (D) Frequencies of SHMs in VH regions of IgE in indicated organs after primary and secondary infection. Data in (B) and (C) show the mean + SEM from two mice per experiment.
Mentions: We further analyzed the overlap of the IgE repertoires in bone marrow, lung, spleen, and LN after primary and secondary infection by NGS analysis to determine the clonal dissemination of IgE+ PCs in these tissues. During primary infection, the IgE repertoires in lung, LN, and spleen showed pronounced overlaps, while the IgE repertoire in the bone marrow was rather unique. However, an increased overlap between the IgE repertoire in the bone marrow and the other organs was observed after secondary infection (Fig 6A and 6B). The IgE repertoires had a high diversity with 300–400 different sequences among 1,000 analyzed sequences in lung, spleen, and LN during primary or secondary infection, whereas the diversity was 2–3-fold lower in the bone marrow (Fig 6C). Similar to the primary infection, the majority of sequences used the VH1/J558 family in combination with DH1 or DH2 segments (S4 and S5 Fig). By analyzing the number of SHMs in the VH region of productive sequences, we observed that during primary infection about 50% of all IgE sequences in all organs contained 0–3 SHMs. During secondary infection, the repertoires were dominated by sequences with 3–20 SHMs reflecting further selection and affinity maturation (Fig 6D).

Bottom Line: The development and persistence of IgE responses are poorly understood, which is in part due to the low number of IgE-producing cells.Together, our results reveal a close relationship between the IgE and IgG1 repertoires in vivo and demonstrate that the memory IgE response is mainly conserved at the level of memory IgG1+ B cells.Therefore, targeting the generation and survival of allergen-specific IgG1+ B cells could lead to development of new therapeutic strategies to treat chronic allergic disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Infection Biology, Institute for Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

ABSTRACT
IgE-mediated activation of mast cells and basophils contributes to protective immunity against helminths but also causes allergic responses. The development and persistence of IgE responses are poorly understood, which is in part due to the low number of IgE-producing cells. Here, we used next generation sequencing to uncover a striking overlap between the IgE and IgG1 repertoires in helminth-infected or OVA/alum-immunized wild-type BALB/c mice. The memory IgE response after secondary infection induced a strong increase of IgE+ plasma cells in spleen and lymph nodes. In contrast, germinal center B cells did not increase during secondary infection. Unexpectedly, the memory IgE response was lost in mice where the extracellular part of IgG1 had been replaced with IgE sequences. Adoptive transfer studies revealed that IgG1+ B cells were required and sufficient to constitute the memory IgE response in recipient mice. T cell-derived IL-4/IL-13 was required for the memory IgE response but not for expansion of B cells from memory mice. Together, our results reveal a close relationship between the IgE and IgG1 repertoires in vivo and demonstrate that the memory IgE response is mainly conserved at the level of memory IgG1+ B cells. Therefore, targeting the generation and survival of allergen-specific IgG1+ B cells could lead to development of new therapeutic strategies to treat chronic allergic disorders.

No MeSH data available.


Related in: MedlinePlus