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Herpes Simplex Virus Type-2 (HSV-2) IgM Enzyme-Linked Immunosorbent Assay (ELISA) Diagnostics Test Kit , Manufacturers from Jei Daniel Biotech Corp.
Extended Data Figure 4: ApoM expression is not required for the lymphopenia response to treatment with FTY720 or the S1P1-specific agonists AUY954 and SEW2871.
Extended Data Figure 5: Multiparameter flow cytometry gating scheme for determination of CLPs and other bone marrow populations.
Extended Data Figure 7: Overexpression of S1P1 results in marked decreases in lymphocyte populations in the thymus and secondary lymphoid organs. Extended Data Figure 9: In vitro lymphopoiesis in the presence of ApoM+ HDL generates B cells at different stages of development. Extended Data Figure 10: Background fluorescence and vascular permeability analysis in brain, spinal cord, and lung. It has been known for several decades that the best antibodies obtained after immunization are relatively 'late' antibodies produced after multiple antigen encounters. There are several important differences between primary and secondary antibody responses, some of which are summarised in the Fig Primary vs secondary antibody responses.
The third difference concerns the isotype of the response: the primary response is dominated by IgM type antibody whereas the seondary and later response are typically dominated by IgG type antibodies. Affinity maturation is due to a process of somatic diversification of the antibody response. Considerable progress has been accomplished in recent years in elucidating the genetic basis of affinity maturation and its underlying processes (somatic hypermutation in mammals, gene conversion in birds). A week after primary immunisation (day 7) the antibody response is dominated by a single pair of VH and VL chain genes (shown as a continuous line in the figure) which encodes an antibody that binds the hapten with uM affinity. A systematic analysis of the binding affinities and kinetics of the anti 2- phenyl oxazolone antibodies has shed some light on the basis for selection (see Fig Maturation of the antobody response to 2=phanyl oxazolone. The main features of the process of somatic hypermutation that occurs in B cells engaged in the response to antigen are listed in the Table Somatic hypermutation of antibody genes and in the Fig VDJ recombination and somatic hypermutation.
The table highlights how the process exhibits extraordinary high rates (10^4 - 10^5 fold higher than basal rates) and selectivity.
The presence of mutational hotspots has also been confirmed in experiment with Vk transgenes.
The process of mutational drift that causes affinity maturation during the antibody response thus represents a somatic process in which successive cycles of mutation and selection in B cells lead to the emergence of rare mutants that bind antigen with very high affinity.
In the last few years studies in three laboratories (Takasu Honjo in Kyoto, Michael Neuberger in Cambridge and Jean-Marie Buerstedde in Munich) have largely clarified the molecular machinery responsible for somatic hypermutation of antibody genes. This work began with the discovery by the Honjo group of an enzyme which they defined activation-induced deaminase (AID) which was induced in germinal centres upon antigenic stimulation, showed significant sequence similarity with apolipoprotein B (apoB) mRNA-editing enzyme, catalytic polypeptide 1 (APOBEC-1) (see Alignment of AID and APOBEC1). One year later Honjo's laboratory reported that over-expression of AID enhanced class-switch recombination in lymphoma cells and that, conversely, AID ablation in mouse blocked class-switch recombination as well as somatic hypermutation.
The sequence homology to other RNA editing enzymes, such as APOBEC-1 and the demonstration that AID had indeed the same activity of APOBEC-1, namely cytidine deamination, led most people to assume that AID worked via RNA editing but M Neuberger and colleagues proposed and demonstrated a different activity, namely activity at the DNA level.


The Fig AID induces DNA mutations in bacteria and its mutator activity is enhanced in ung- strains shows that E coli cells transformed with a plasmid encoding human AID led to ~ 8 fold increase in mutants at the rpoB locus (conferring rifampicin resistance) as measured by fluctuation analysis. Somatic hypermutation, however, leads to both transitions and transversions as shown above in the Fig VDJ recombination and somatic hypermutation. It has already been mentioned that in the presence of a functional uracil-DNA glycosylase, cells efficiently remove the dU generated through the activity of AID leading to the generation of an abasic site that can repaired in three steps, namely through the activity of a apyrimidinic (AP) endonuclease (APEX1), followed by DNA polymerase beta (POLBB) and finally by ligase III (LIG3).
The studies summarised above provide a clear picture of how somatic hypermutation operates at dC-dG pairs. There is strong evidence that a number of enzymes are involved in the so-called phase 2 (dA-dT) of somatic hypermutation. Patch repair occurs by degrading a short patch of DNA on the damaged strand and repairing it using the opposite strand as template.
These observations provided the motivation for unveiling a complex set of genetic events which account for our current understanding of the maturation of the antibody response. Thus between the primary and the secondary response a phenomenon of isotype switch takes place. This concept has captivated the the mind of a number of immunologists and geneticists for a number of years and was clearly laid out by J Lederbergin 1959 as a consequence of high-rate of mutation in antibody producing cells. This progress has resulted initially from hybridoma-based sequence studies of the response to simple haptens.
However, at later stages of the immune response, ie late primary (day 14) or secondary two events take place.
It also emphasizes that the targeting of the somatic hypermutation is not provided by sequences in the V segments because, in transgenic experiments, other genes become mutated if inserted in place of the V segment.
These notwithstanding, it is clear that mutations are distributed across both CDRs and framework segments and that antigen selction is responsible for the subset of mutations observed in affinity-matured antibodies. APOBEC-1 catalyses the deamination of a C to U at codon 2153 in the primary apoB transcript in the intestine thus generating an in frame stop codon (CAA to UAA). Independent studies by Buerstedde and colleagues established that AID was essential for antibody gene conversion in chicken. The Fig also shows that, if the experiment is carried out in cells deficient in uracil-DNA glycosylase (ung-), the enzyme that plays an initial and critical role in repairing AID-induced cytidine deamination, the number of mutants is higher.
A summary of the domain organisation of the AID protein and mutations occurring in patients with defects in AID activity is shown in the Fig Functional domains of the AID protein.
It should be stressed that common procedures for establishing the titre of the antibody response are confounded by the affinity issue (see below). The fourth and final difference concerns the affinity (ie the strength) of the binding of the antibody to its antigen.
In 1966 S Brenner and C Milstein provided additional strength to the somatic hypothesis by suggesting a mechanism for somatic hypermutation, namely error prone repair by DNA polymerase of strand breaks produced within the immunoglobulin genes. In the most comprehensive of such studies, carried out by C Milstein and colleagues, inbred mice were immunised with the hapten 2-phenyl-oxazolone and the antibody response studied by immortalising individual B cells, sequencing the RNA of their H and L chain determining equilibrium and kinetic constants of these antibodies.


The first is that the original pair of VH and VL genes is replaced by an array of somatic mutants (mutations are shown as vertical bars across the sequence if silent or as lollipops if coding) (see Fig Maturation of the antobody response to 2=phanyl oxazolone. The figure shows the Ka (Keq) values for antibodies encoded by the original VH and VL pairs (blue circles), or by different genes (orange circles) or by either the original VH or VL segment in association with another chain (green circles). As a result the intestinal protein (apoB48, 2152) is truncated whereas in liver the same transcript is not deaminated and a full translation product is produced (apoB100, 4563 aa). Thus in the short period of three years AID went from initial discovery to a central role in the three major processes of somatic diversification of antibody genes. These data thus provided direct and strong evidence for activity of AID at the DNA level and for the ability of this enzyme to direct dC to dT transitions during antibody affinity maturation. There is evidence that other enzymes and processes are involved causing the additional mutations. The patients in question either produce a truncated protein (shown with asterisks in the Fig at positions of truncations) or carry missense mutations, the most frequent of which involves R112. Circles represent mean value acquired from three mice in independent experiments; bars represent means. Even allowing for this technical issue, however, the amount of specific antibody produced during secondary responses is higher than in primary. Both the somatic mutants of the initial H and L chain pair and the antibodies encoded by alternative gene combinations have affinities up to 1,000 fold higher than the original pair.
These patients all display a hyper-IgM syndrome, the severity of which depends on the type of AID mutation (as will be discussed in more detail in the lecture on immunodeficiencies. CLPs, gated according to the gating hierarchy shown in a, were sorted from the bone marrow of wild-type mice and incubated in methylcellulose medium containing growth factors to support both lymphoid and myeloid lineage development. Arrows indicate amplified DNA fragments corresponding to undeleted or deleted segments d–f, Four days after the final dose of tamoxifen, CD4+, CD8+ and CD19+ cells in brachial and inguinal lymph nodes (d) and spleen (e), and thymic CD4+ CD8+ double-positive (DP), CD4+ and CD8+ single-positive (CD4 or CD8 SP), total double-negative (DN), and double-negative subpopulations DN2, DN3 and DN4 (f) were quantified by flow cytometry in S1pr1 OE mice and wild-type littermates. Thus there is a complex set of differences between the response to the first antigenic challenge and the subsequent (so called anamnestic) ones. So why is there a shift to different gene combinations if the affinity of the original pair can be built to similar values ? The data available suggest that kinetic parameters rather than straightforward thermodynamic ones appear to drive selection during maturation. Twenty-four hours after treatment, CD4+, CD8+ and CD19+ cells in the blood were quantitated by flow cytometry. CD11b+ cells serve as negative controls, since they do not have IL-7R and therefore do not respond to IL-7 stimulation with Stat5 phosphorylation.



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