2. similarly, mutant igm that cannot activate complement does not enhance the immune response. a possible explanation for igm-mediated enhancement is that b lymphocytes capture igm-antigen-complement complexes and transport the complexes into areas in the spleen where efficient immune responses are generated. because igm is produced early in an immune response, this might be important in the initiation of antibody responses. synthesis in germ-line cells (sperm and ova) the genes that will eventually encode immunoglobulins are not in a functional form (see v(d)j recombination). in the case of the heavy chain, three germ-line segments denoted v, d and j are ligated together and adjoined to the dna encoding the µ heavy chain constant region. early in ontogeny, b cells express both the µ and the δ heavy chains; co-expression of these two heavy chains, each bearing the same v domain depends on alternative splicing and alternative poly-a addition sites. the expression of the other isotypes (γ, ε and α) is affected by another type of dna rearrangement, a process called immunoglobulin class switching. clinical significance igm is the first immunoglobulin expressed in the human fetus (around 20 weeks) and phylogenetically the earliest antibody to develop. igm antibodies appear early in the course of an infection and usually reappear, to a lesser extent, after further exposure. igm antibodies do not pass across the human placenta (only isotype igg). these two biological properties of igm make it useful in the diagnosis of infectious diseases. demonstrating igm antibodies in a patient's serum indicates recent infection, or in a neonate's serum indicates intrauterine infection (e.g. congenital rubella syndrome). the development of anti-donor igm after organ transplantation is not associated with graft rejection but it may have a protective effect. igm in normal serum is often found to bind to specific antigens, even in the absence of prior immunization. for this reason, igm has sometimes been called a "natural antibody". this phenomenon is probably due to the high avidity of igm that allows it to bind detectably even to weakly cross-reacting antigens that are naturally occurring. for example, the igm antibodies that bind to the red blood cell a and b antigens might be formed in early life as a result of exposure to a- and b-like substances that are present in bacteria or perhaps also in plant materials. igm antibodies are mainly responsible for the clumping (agglutination) of red blood cells if the recipient of a blood transfusion receives blood that is not compatible with their blood type. a mutation of the mu chain within igm causes autosomal recessive agammaglobulinemia. the presence of igm or, rarely, igg is one of the obligate criteria for a diagnosis of schnitzler's syndrome.