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C H A P T E R 25

TOLERANCE AND AUTOIMMUNITY

Taku Kambayashi

The role of the immune system is to eliminate potential threats specifically binds to one pathogen but not another? How can the
invading the organism from the environment and from those that are immune system generate a T cell that can specifically kill a pathogen-
generated within the organism. Examples of environmental threats infected cell while sparing noninfected cells? To mount responses
include pathogens and toxins, whereas internal threats include neo- with such specificity, the receptors that activate adaptive immune
plastic transformation and inadvertently formed toxic metabolites. cells (T and B cells) must be created with enormous diversity. The
To function properly, the immune system must be able to balance B-cell receptor (BCR) and T-cell receptor (TCR) genes are encoded in
the capacity to mount a response against true threats that may pose pieces (V, D, and J segments) that rearrange in the DNA of precursor
harm to the organism, while being tolerant to those that should be lymphocytes to ultimately form a complete gene (VDJ recombina-
ignored including commensals, inert environmental antigens, and tion). This process allows for many possible gene segment combina-
antigens that are derived from normal self. A complex and multi- tions (e.g., 4000 different ones for the human immunoglobulin [Ig]
layered approach has evolved to successfully handle this problem. heavy chain alone), and in addition, small deletions and random
However, hypersensitivity reactions, in which this balance is upset, additions at the sites where the pieces are joined together create
are remarkably common in the population. Autoimmunity is a subset additional diversity. Inevitably, autoreactive lymphocytes are formed
of such hypersensitivity reactions, whereby the immune system loses as a consequence of this rather random process of TCR and BCR
tolerance to a particular self-derived antigen and starts to attack the generation. Hence diversity is generated at the expense of creating
organism itself. The diversity and variable severity of such diseases autoreactive lymphocytes. There are two implications of this process
most likely reflects the various approaches the immune system takes for self-tolerance. First, it is impossible to prevent the assembly of
to regulate self-directed responses and thereby the various points at a self-reactive receptor by filtering these out of the germline gene
which this multilayered system can break down. The normal func- repertoire. Second, a developing lymphocyte cannot be considered
tions that prevent autoimmune disease are collectively known as autoreactive until the assembly process is complete and the BCR
self-tolerance mechanisms. or TCR is expressed. Thus autoreactive lymphocytes are produced
Autoimmune diseases are relevant to hematology at several levels, every day, and it is at this key developmental stage—when the BCR
as autoimmune responses can be directed towards the hematopoietic or TCR is first expressed by the cell—that the immune system can
system. For example, autoimmune hemolytic anemia (AIHA) and first eliminate these potentially harmful cells. For B cells, this occurs
idiopathic thrombocytopenic purpura (ITP) are diseases in which in the BM, the primary central lymphoid organ (Fig. 25.1); for T
antibodies are spontaneously made against red blood cells (RBCs) cells, it occurs in the thymus (Fig. 25.2). The process is thus termed
and platelets, respectively. In some cases, the RBC and platelet central tolerance and is described in further detail later.
autoantibodies are not generated spontaneously but are induced
by transfusion: these include posttransfusion purpura (PTP) and
possibly AIHA associated with transfused thalassemia. Other hema- Regulation: Central Tolerance
topoietic components such as the bone marrow (BM) and neutrophils
are targeted in aplastic anemia and in autoimmune neutropenia, Clonal Deletion: B Cells
respectively. However, the target does not necessarily have to be
a cellular component. In acquired thrombotic thrombocytopenic The classic experiments of Nossal and Pike were the first to demonstrate
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purpura (TTP), an autoantibody is generated against an enzyme that developing autoreactive B cells can be eliminated in the BM.
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known as a disintegrin and metalloproteinase with thrombospondin The details of this process remained murky until the Goodnow and
motifs, member 13 (ADAMTS13), which results in the accumulation Nemazee groups each developed a BCR transgenic mouse system for
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of ultra large von Willebrand factor (UL-VWF) fragments that lead the study of self-tolerance. These mice have been genetically altered
to microangiopathic hemolytic anemia (MAHA). Finally, although to carry the preformed Ig variable (V) genes that encode a specific
not a classic autoimmune disease, graft-versus-host disease (GVHD), autoantibody. The presence of this preformed transgene short circuits
a common complication of allogeneic stem cell transplantation and prevents the normal rearrangement process at the natural Ig gene
whereby allogeneic donor T cells attack recipient tissues, shares many loci. Thus each B cell in the animal expresses only the transgene and
features with autoimmune syndromes. has the same specificity. By choosing a target antigen that is carried by
An important principle in understanding the etiology of only some strains of mice (e.g., the polymorphic major histocompat-
autoimmune diseases is that no special mechanism, cell, antibody ibility complex [MHC] class I genes used by Nemazee), it is possible
type, or reaction is specific to autoimmune diseases. Rather, the to render the transgenic B cells autoreactive when crossed onto one
pathogenesis involves the inappropriate or dysregulated triggering of strain (Fig. 25.3) but not autoreactive in a different strain. The results
the normal mechanisms of immunity. Therefore an understanding of such systems were dramatic. A complete loss or deletion of the B
of autoimmune disease induction and pathogenesis requires a firm cells was demonstrated in the strain of mice that had the autoantigen,
grounding in the basic immune cell functions and interactions, which but perfectly good expression of the B cells was observed when the
can be found in the preceding chapters. autoantigen was absent. Furthermore, it was shown that this deletion
occurred at the immature B-cell stage, just when the cells first express
their BCR. It has been since discovered that deletion is just the final
SELF-REACTIVE LYMPHOCYTES: ORIGIN AND CONTROL step in controlling autoreactive B cells. B cells that have completed
H- and L-chain rearrangement and then recognize self-antigen while
One challenge that the adaptive immune system faces is the immense still immature in the BM may actually undergo a second round of
variety of molecules that it needs to specifically mount responses V gene rearrangement. This most likely occurs at the L-chain loci,
against. How can the immune system generate an antibody that which are particularly suited to secondary V to J rearrangements.

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