Pathology > Basic Hematology > White Cell Disorders > Immunosecretory Disorders

Immunosecretory Disorders

Welcome to the Immunosecretory Disorder section. This section is divided into three subsections:

  • Introduction
  • Myeloma,
  • Other Monoclonal Gammopathies
  • Questions

The Introduction to Immunosecretory Disorders which begins below contains basic definitions, a review of B lymphocytes, and an overview of monoclonal gammopathies.

 

Immunosecretory Disorders: Introduction

Immunosecretory disorders or plasma cell dyscrasias are proliferations of plasma cells and/or plasmacytoid lymphocytes associated with a monoclonal production of immunoglobulin or a monoclonal gammopathy.

In the above serum protein electophoresis gel and densitometry tracing we see a large abnormal peak or "spike" in the b position. The height and narrowness of the peak indicate a homogeneous or monoclonal protein. Compare with a normal serum electrophoresis.

Monoclonal (M) "spikes" usually occur in either the b or g regions. An individual plasma cell produces only one type of light chain, either k or l light chain, but never both. In plasma cell disorders a clone of cells produces a single light chain type, either k or l .

Information on B cell maturation, Ig gene rearrangements, Ig structure, and on individual immunoglobulins IgM, IgD, IgG, IgA, IgE may be reviewed at this time.

 

In plasma cell disorders a clone of cells produces a single light chain type, either k or l . If the clone is large enough, sufficient immunoglobulin is produced to be visible as a "spike" on gel electrophoresis, identifying a monoclonal population of cells.

Nearly all malignant cell populations are monoclonal, where as nearly all reactive populations are polyclonal.

In a reactive state, antigen is presented to multiple lymphocytes each of which will make a slightly different antibody. Some lymphocytes/plasma cells will make k light chains and some will make l light chains. Even among all the l producing cells, most individual cells each make a slightly different antibody, producing increased amounts of heterogeneous immunoglobulins, or a (polyclonal gammopathy).

Immunosecretory Disorders: Introduction-Clonality

 

Immunosecretory Disorders: B Lymphocyte Development

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Ig Gene Rearrangements

Immunoglobulin genes are found on several different chromosomes:

Chromosome 14

Heavy chian gene

Chromosome 2

Kappa light chain gene

Chromosome 22

Lambda light chain gene

Even on one chromosome the immunoglobulin genes are organized as discontinuous DNA segments along the gene (germline configuration). The separated DNA segments in both the heavy and light chain genes are the variable (V) regions, the joining (J) regions and the constant (C) regions. The heavy chain genes also include a diversity (D) region.

A series of sequential gene rearrangements, transcription, and translation events take place, beginning at the time when a lymphoid stem cell commits to becoming a B cell progenitor.

 

Rearrangement of the heavy (H) chain gene begins the process by which lymphoid precursors develop into functioning B lymphocytes and produce Ig.

The process begins on chromosome 14 where (1) a DH region must first rearrange with a JH region and, if successful, then (2) rearrange with a VH region to produce a VH/DH/JH segment*. During RNA transcription (3) splicing joins the VH/DH/JH segment to one of the eight constant regions which are, in order, Cm; Cd; Cg3; Cg1; Ce2; Ca1; Cg2; Cg4; Ce1, and Ca2. Cm is closest to the JH region.

* The need for two successful rearrangements (steps1&2) to produce a VH/DH/JH segment, requires in most (>80%) cases the rearrangement of both heavy chain alleles, as the first attempt is often not successful.

 

At time of transcription, intervening sequences (introns) are removed by RNA splicing. The addition of polyA and the splicing of secretory or membranous sequences dictates production of secretory (cytoplasmic) Ig or membranous (surface) Ig or both.

Following transcription, the messenger RNA is translated into a completed heavy chain protein.

Initially B cells produce an immunoglobulin with a heavy chain of the m Ig class as the m gene is closest to the JH region.

Synthesis of a m heavy chain from the first allele blocks rearrangement of the other chromosome (allelic exclusion). If the cell fails to achieve a successful m recombination, it is presumed to die. Furthermore, production of m is necessary for light chain rearrangement to take place (next ).

 

The assembly of the kappa gene (short arm of chromosome 2) is successful in about 60% of human B lymphocytes. Each of the Vk segments is accompanied by a leader (L) sequence. The Vk segments encode the first 95 N-terminal amino acids. Positions 96 -108 are encoded by one of five joining (Jk) gene segments. The constant (Ck) portion of the kappa light chain (amino acids 109 - 214) is encoded by a single constant (Ck) region separated from the Jk region by an intervening sequence or intron.

DNA rearrangement (1) places a single Vk segment directly adjacent to one of five Jk segments. During transcription (2), introns are removed by RNA splicing. Then messenger RNA is translated into a completed kappa light chain protein. If a k rearrangement was successful, future l rearrangement is blocked and the l genes remain germline.

 

Should both the two kappa alleles fail to successfully rearrange to form a Vk/Jk segment, an attempt is made to assemble a light chain segment using lambda genes. Thus in approximately 40% of cells a rearrangement process takes place on chromosome 22 where the lambda light chain gene is located.

The major difference between kappa and lambda genes is that rather than a single Ck region as found with kappa, the lambda gene contains six Cl regions each associated with a particular Jk region.

Again, rearrangement of the DNA places a single Vl segment directly adjacent to one of six Jl segments. During transcription, any intervening sequences are removed by RNA splicing, following which the messenger RNA is translated into a completed lambda light chain protein.

 

If k rearrangement fails and a successful l rearrangement takes place, the k genes are either aberrantly rearranged or deleted entirely. As with failure of heavy chain recombination, if all k and l attempts at recombination fail, the cell is thought to die.

Light chain allelic exclusion allows a B lymphocyte to make only one type of antibody.

Once a successful light chain, (kappa or lambda), is produced it is attached to the heavy chain (usually m) for either secretion or membrane insertion.

At first B cells produce an immunoglobulin with a heavy chain of either the m or in some instances m and d. Later a more distally located constant region can be moved into proximity with the already assembled VH/DH/JH segment. This heavy chain class switch allows identical VH/DH/JH antigen specificity to be expressed with different constant regions. Thus effect or function varies, but with the same antibody specificity. See B cell maturation.

 

The B lymphocyte gene rearrangements are the means by which B cells respond to untold numbers of antigens, producing millions of different B cell clones. This diversity arises from the almost limitless recombinations allowed by the variable, diversity, and joining genes; by junctional diversity, and by variable gene somatic mutations (resulting in affinity maturation in antibody responses).

The molecular genetics of B lymphocytes is linked to B cell growth, differentiation, and response including immumoglobulin production. B cell growth and immunoglobulin production is similar in plasma cell disorders, but is uncontrolled and lacks antigenic stimuli.

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Ig Gene Structure

The Ig monomer at left consists of two identical proteins (dimers), each of which has a heavy chain and a light chain. The components are linked by disulfide bonds. At one end of Ig (on both the H &L chains) is the variable (V) region, while at the other end is the constant (C) region.

The V region is the antigen recognition site containing sequences unique to a specific Ig molecule.

The C region contains the Fc (crystallizable fragments) portion of the Ig molecule binding Ig to the cell and causing activation of complement. The C region is divided into discrete domains: C1, C2, C3, etc.

Within the V region, both the H chain and the L chain contain hypervariable regions of highly variable amino acid sequences.

This Ig monomer is the basic structural component of the 5 different Ig types or major classes: IgM, IgD, IgG, IgA,and IgE.

The IgM, IgD, IgA, and IgE immunoglobulins are associated with carbohydrate moieties.

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