Anti-Hu antibodies

Synonyms: Anti-neuronal nuclear antibody type 1 (ANNA-1)

Clinical associations: see figure 1

Figure 1

Tumor associations see figure 2. Extrathoracic tumors included in order of frequency: prostate, gastrointestinal, breast, bladder, pancreas, and ovary.

Figure 2

Frequency of anti-Hu antibodies in patients with suspected paraneoplastic neurological syndromes (PNS) without evidence of cancer after >5 years of follow-up: 2%

Frequency of anti-Hu antibodies in patients with small-cell lung cancer without PNS:
1% with titers similar to those of patients with PNS, 16% with low titers.

Screening test:
Immunohistochemistry on frozen brain sections (human, monkey, rabbit, rat, mouse) (figure 3).

Confirmatory test:
Several commercial tests using immunoblots of recombinant HuD protein. Immunoblot of neuronal homogenates (figure 3)

Figure 3

Immunologic associations:
Patients with paraneoplastic syndromes and anti-Hu antibodies may develop concurrent antibodies to other onconeuronal antigens. They include, anti-CV2 (CRMP5), anti-amphiphysi, anti-Ri, anti-VGCC, or anti-Zic4 antibodies.

Hu antigens

The target of anti-Hu antibodies is a family of ~35- 40 kDa RNA-binding proteins that are mainly expressed in the nervous system. The three human neuronal Hu antigens are HuD, HuC and Hel-N1 and all 3 are recognized by sera or CSF of all patients with anti-Hu antibodies. There is a fourth Hu protein called HuR, which expression is not restricted to neurons and is inconsistently recognized by paraneoplastic anti-Hu antibodies. The Hu proteins contain three RNA-binding domains that are homologous to those of a drosophila protein, called ELAV. While ELAV is critical for the development of the fly nervous system, the Hu proteins are also critical for the development and maintenance of the neuronal phenotype in mammals. The human Hu proteins are expressed by small-cell lung cancers and most neuroblastomas.

References

1. Graus F, Keime-Guibert F, Reñé R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001;124:1138-48.
2. Musunuru K, Darnell RB. Paraneoplastic neurological disease antigens:RNA-binding proteins and signaling proteins in neuronal degeneration. Annu Rev Neurosci 2001;24:239-62.
3. Posner JB, Dalmau J. Paraneoplastic syndromes. Curr Op Immunol 1997;9:723-9.
4. Bataller L, Wade DF, Graus F, Stacey HD, Rosenfeld MR, Dalmau J. Antibodies to Zic4 in paraneoplastic neurologic disorders and small-cell lung cancer. Neurology 2004; 62: 778-82.

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